Exome Sequencing and the Identification of New Genes and Shared Mechanisms in Polymicrogyria.

Importance: Polymicrogyria is the most commonly diagnosed cortical malformation and is associated with neurodevelopmental sequelae including epilepsy, motor abnormalities, and cognitive deficits. Polymicrogyria frequently co-occurs with other brain malformations or as part of syndromic diseases. Past studies of polymicrogyria have defined heterogeneous genetic and nongenetic causes but have explained only a small fraction of cases. Objective: To survey germline genetic causes of polymicrogyria in a large cohort and to consider novel polymicrogyria gene associations. Design, Setting, and Participants: This genetic association study analyzed panel sequencing and exome sequencing of accrued DNA samples from a retrospective cohort of families with members with polymicrogyria. Samples were accrued over more than 20 years (1994 to 2020), and sequencing occurred in 2 stages: panel sequencing (June 2015 to January 2016) and whole-exome sequencing (September 2019 to March 2020). Individuals seen at multiple clinical sites for neurological complaints found to have polymicrogyria on neuroimaging, then referred to the research team by evaluating clinicians, were included in the study. Targeted next-generation sequencing and/or exome sequencing were performed on probands (and available parents and siblings) from 284 families with individuals who had isolated polymicrogyria or polymicrogyria as part of a clinical syndrome and no genetic diagnosis at time of referral from clinic, with sequencing from 275 families passing quality control. Main Outcomes and Measures: The number of families in whom genetic sequencing yielded a molecular diagnosis that explained the polymicrogyria in the family. Secondarily, the relative frequency of different genetic causes of polymicrogyria and whether specific genetic causes were associated with co-occurring head size changes were also analyzed. Results: In 32.7% (90 of 275) of polymicrogyria-affected families, genetic variants were identified that provided satisfactory molecular explanations. Known genes most frequently implicated by polymicrogyria-associated variants in this cohort were PIK3R2, TUBB2B, COL4A1, and SCN3A. Six candidate novel polymicrogyria genes were identified or confirmed: de novo missense variants in PANX1, QRICH1, and SCN2A and compound heterozygous variants in TMEM161B, KIF26A, and MAN2C1, each with consistent genotype-phenotype relationships in multiple families. Conclusions and Relevance: This study's findings reveal a higher than previously recognized rate of identifiable genetic causes, specifically of channelopathies, in individuals with polymicrogyria and support the utility of exome sequencing for families affected with polymicrogyria.

Tele-neuropsychology in culturally and linguistically diverse populations within the U.S. and U.S. territories: A scoping review1.

Objective: Tele-neuropsychology (teleNP) has the potential to deliver assessment to people who face limited access to culturally and linguistically appropriate services, health disparities, and negative social determinants of health (SDOH). We reviewed to what extent teleNP has been examined in racially and ethnically diverse samples within the U.S. and U.S. territories and describe validity, feasibility, barriers, and facilitators. Method: A scoping review was conducted to examine factors relevant to teleNP with racially/ethnically diverse samples, using Google Scholar and PubMed®. Key words referenced "tele-neuropsychology," racial/ethnic populations within the U.S. and territories, and relevant constructs (e.g. "validity," "feasibility"). Studies included in the final analysis were empirical, addressed teleNP, and included racially/ethnically diverse individuals within the U.S. The search resulted in 10,312 articles total, with 9,670 following removal of duplicates. We excluded 9,600 following abstract review, and an additional 54 articles following full-text review. Thus, 16 studies were included in the final analysis. Results: Results showed the greatest number of studies supporting feasibility and utility of teleNP with older LatinX/Hispanic adults. Limited reliability and validity data suggested that, for the most part, teleNP and face-to-face neuropsychological evaluations were broadly equivalent, and no studies contraindicated use of teleNP in culturally diverse populations. Conclusions: This review provides preliminary support, particularly in terms of teleNP feasibility, with culturally diverse individuals. Current research is hampered by low inclusion of culturally diverse individuals and limited studies, and while support is nascent, these findings should be balanced with promotion of healthcare equity/access.

Impaired catabolism of free oligosaccharides due to MAN2C1 variants causes a neurodevelopmental disorder.

Free oligosaccharides (fOSs) are soluble oligosaccharide species generated during N-glycosylation of proteins. Although little is known about fOS metabolism, the recent identification of NGLY1 deficiency, a congenital disorder of deglycosylation (CDDG) caused by loss of function of an enzyme involved in fOS metabolism, has elicited increased interest in fOS processing. The catabolism of fOSs has been linked to the activity of a specific cytosolic mannosidase, MAN2C1, which cleaves α1,2-, α1,3-, and α1,6-mannose residues. In this study, we report the clinical, biochemical, and molecular features of six individuals, including two fetuses, with bi-allelic pathogenic variants in MAN2C1; the individuals are from four different families. These individuals exhibit dysmorphic facial features, congenital anomalies such as tongue hamartoma, variable degrees of intellectual disability, and brain anomalies including polymicrogyria, interhemispheric cysts, hypothalamic hamartoma, callosal anomalies, and hypoplasia of brainstem and cerebellar vermis. Complementation experiments with isogenic MAN2C1-KO HAP1 cells confirm the pathogenicity of three of the identified MAN2C1 variants. We further demonstrate that MAN2C1 variants lead to accumulation and delay in the processing of fOSs in proband-derived cells. These results emphasize the involvement of MAN2C1 in human neurodevelopmental disease and the importance of fOS catabolism.

Detection of high-risk carbapenem-resistant Klebsiella pneumoniae and Enterobacter cloacae isolates using volatile molecular profiles.

Infections caused by carbapenem-resistant Enterobacteriaceae (CRE) are alarming in the clinical setting, as CRE isolates often exhibit resistance to most clinically-available antibiotics. Klebsiella pneumoniae carbapenemase (KPC) is the most common carbapenemase carried by CRE in North America and Europe, frequently detected in isolates of K. pneumoniae, Escherichia coli, and Enterobacter cloacae. Notably, KPC-expressing strains often arise from clonal lineages, with sequence type 258 (ST258) representing the dominant lineage in K. pneumoniae, ST131 in E. coli, and ST78 and ST171 in E. cloacae. Prior studies have demonstrated that carbapenem-resistant K. pneumoniae differs from carbapenem-susceptible K. pneumoniae at both the transcriptomic and soluble metabolomic levels. In the present study, we sought to determine whether carbapenem-resistant and carbapenem-susceptible isolates of K. pneumoniae, E. coli, and E. cloacae produce distinct volatile metabolic profiles. We were able to identify a volatile metabolic fingerprint that could discriminate between CRE and non-CRE with an area under the receiver operating characteristic curve (AUROC) as high as 0.912. Species-specific AUROCs were as high as 0.988 for K. pneumoniae and 1.000 for E. cloacae. Paradoxically, curing of KPC-expressing plasmids from a subset of K. pneumoniae isolates further accentuated the metabolic differences observed between ST258 and non-ST258.

Copper Deficiency Myelopathy After Upper Gastrointestinal Surgery.

A well-functioning alimentary canal is required for adequate nutrient absorption. Disruption to the upper gastrointestinal tract through surgery can lead to micronutrient malnourishment. Copper deficiency has been noted in up to 10% of those undergoing Roux-en-Y gastric bypass surgery, but sequalae are not frequently reported. The resultant deficiency states can have profound and long-term consequences if not realized early and managed appropriately. Here we present a case of copper deficiency myelopathy, a condition indistinguishable from subacute combined degeneration of the spinal cord, following upper gastrointestinal bypass surgery for gastric ulceration, further complicated by inadequate nutrition.

Effects of alcohol-based hand hygiene solutions on breath alcohol detection in the emergency department.

This study aimed to investigate the effects of alcohol-based hand hygiene solution (ABHS) use by care providers on point-of-care alcohol breath analyzer interpretation under different clinically relevant conditions. Among each test condition (foam vehicle with immediate testing, gel vehicle with immediate testing, allowing hands to dry after the use of ABHS, and donning gloves after the use of ABHS), alcohol was detected in breath at 1 minute after use of ABHS. Because the use of ABHS by individuals administering breath alcohol detection may result in false-positive detection of alcohol, staff using these devices should consider traditional hand hygiene with soap and water.

The effect of wavelength on endothermal heat-induced thrombosis incidence after endovenous laser ablation.

OBJECTIVE: We hypothesized that the incidence of endothermal heat-induced thrombosis (EHIT) depends on the laser wavelength used in endovenous laser ablation (EVLA) of the saphenous veins. METHODS: We identified patients undergoing EVLA in our office from 2005 to 2014 with an 810-nm (hemoglobin-specific) or 1470-nm (water-specific) laser. We reviewed the records for age, sex, body mass index, Clinical, Etiologic, Anatomic, and Pathophysiologic (CEAP) class, vein diameter, vein(s) treated, adjunctive phlebectomy, energy delivered, laser pullback times, and EHIT (closure level ≥3) development. The Fisher exact test and Pearson χ(2) test were used to evaluate the association between EHIT and the categoric variables. Logistic regression was used to evaluate the relationship between EHIT and the continuous variables. RESULTS: There were 1439 veins ablated in 1109 patients (769 female, 340 male). The great saphenous vein (GSV) was treated in 1332, the small saphenous vein (SSV) in 78, and both in 29 (22 procedures on accessory veins were excluded). The CEAP C class for these patients was 1 in 0, 2 in 616, 3 in 522, 4 in 150, 5 in 51, and 6 in 98, and was not recorded in 2. EHIT occurred in 76 cases (5.28%), in 73 after GSV ablation and in three after SSV ablation. The 810-nm laser was used in 1144 procedures, and EHIT developed in 69 patients (6.0%). The 1470-nm laser was used in 295 procedures, with EHIT developing in seven patients (2.4%; P = .0122 by Fisher exact test). The average energy delivered to the EHIT group (3517 ± 1998.1 J) was higher than for the non-EHIT group (2825.1 ± 1491.2 J; P = .0002). The average vein diameter was larger in the EHIT group (9.3 ± 3.8 mm) than in the non-EHIT group (7.2 ± 3.3 mm; P = .0001). EHIT occurred in 59 of 837 cases (6.6%) undergoing simultaneous stab phlebectomy compared with 17 of 525 cases (3.1%) undergoing only EVLA (P = .0049). Statistical analysis confirmed the association between EHIT and CEAP class was significant (P = .0001). No differences were seen for age, body mass index, sex, combined bilateral, and multiple or simultaneous GSV and SSV ablations between the two groups. A multivariate analysis confirmed that CEAP class, vein diameter, adjunctive phlebectomy, and laser wavelength were indeed risk factors for post-EVLA EHIT and that energy delivered and pullback time were not. CONCLUSIONS: Water-specific laser fiber wavelength (1470 nm) reduces the risk of EHIT compared with a hemoglobin-specific wavelength (810 nm). CEAP class, simultaneous phlebectomy, and vein diameter >7.5 mm are associated with increased risk of EHIT after EVLA.

The incidence and outcome of endothermal heat-induced thrombosis after endovenous laser ablation.

BACKGROUND: Endovenous laser ablation (EVLA) of the saphenous vein has become one of the preferred treatments for treating saphenous vein reflux that has resulted in symptomatic lower extremity venous insufficiency or varicose veins. This procedure was noted during initial reports to have a low incidence of postoperative thrombosis of the femoral or popliteal vein adjacent to the treated great saphenous vein (GSV) or small saphenous vein (SSV). Later clinical experience suggested that the actual incidence of this event is higher and it was subsequently termed endothermal heat-induced thrombosis (EHIT). METHODS: We reviewed the office records and the pre- and post-treatment ultrasounds of patients undergoing EVLA in our office from 2005 to 2010 to determine the frequency of EHIT in patients we had treated and then graded them according to a previously published classification. RESULTS: There were 528 veins treated in 192 men and 336 women. The clinical, etiology, anatomy, pathophysiology (CEAP) class for these patients was 1 (0), 2 (291), 3 (65), 4 (104), 5 (26), and 6 (40), respectively. The GSV was treated in 496 patients, the SSV in 22, and both were treated in 10 patients. EHIT occurred in 29 of the legs treated for an incidence of 5.1%. The EHIT in the femoral vein were of level 3 (3), 4 (7), 5 (12), and 6 (3), respectively. Two patients developed EHIT in the popliteal vein after EVLA of the SSV. Treatment for the EHIT consisted of observation (13), anticoagulation (9), antiplatelet therapy (2), and nonsteroidal anti-inflammatory agents (1). Duration of therapy was usually 1 week, but 7 patients were treated for periods ranging from 1 to 7 weeks. No pulmonary emboli occurred in any of these patients. The EHIT resolved completely in all patients. CONCLUSIONS: EHIT after EVLA occurs frequently and mainly consists of low-risk level 3, 4, and 5 deep vein thrombosis. The risk of pulmonary embolism is low and the EHIT typically resolves after 1 week. It can be treated with a short course of antiplatelet or anticoagulation therapy, although observation appears to be sufficient as well for lesser grades of EHIT.

Construct validity and extended normative data for older adults for the Brief Visuospatial Memory Test, Revised.

PURPOSE: This study examined the construct validity of a visual memory test (Brief Visuospatial Memory Test, Revised [BVMT-R]) in a sample of older adults and provided normative data for adults aged 80+ years. METHOD: The sample included 109 community-dwelling individuals (mean [M] age = 74.9 years, M education = 15.0 years, 62.4% female, and 97.2% European American). PROCEDURES: Measures administered included the BVMT-R, California Verbal Learning Test, 2nd edition, and subtests of the Delis-Kaplan Executive Function System and Neuropsychological Assessment Battery. RESULTS: The BVMT-R correlated highly with another measure of memory and less so with unrelated measures (e.g., verbal fluency). Age and education were significantly correlated with BVMT-R Total and Delayed Recall scores, with education as the strongest predictor. No significant differences were found for sex. Normative data were provided for adults aged 80 to 88 years (n = 29). CONCLUSIONS: Adequate evidence was found for convergent validity and only partial support for discriminant validity. Normative data should continue to be stratified by age and also by formal education level.

Prevalence of cognitive impairment, depression, and anxiety symptoms among older adults with glaucoma.

PURPOSE: Two factors which may disrupt the ability to adhere to the treatment for glaucoma are cognitive impairment and mental health complications. Poor adherence to treatment may lead to preventable vision loss. Past research in this area has been limited by little focus on older patients with glaucoma, and the use of brief measures of cognition that may not detect subtle deficits related to Alzheimer disease. PATIENTS AND METHODS: This study examined the prevalence of cognitive impairment, depression, and anxiety in a sample of 41 glaucoma patients at a tertiary care glaucoma clinic. They had a mean age of 70.0 years (SD=9.2 y; range: 51 to 86 y) and 70% (n=30) were female. Two cognitive measures commonly used in detecting dementia were used to measure cognitive functioning. RESULTS: Controlling for age, memory impairment was found in approximately 20% of the sample, and impaired executive functioning was found in approximately 22% of the sample. Forty-four percent of the sample scored in the impaired range on one or more measures. Mild-to-moderate depressive symptoms were found in 12.2% of participants, and 1 person reported clinically significant anxiety. CONCLUSIONS: The results from this study indicate that cognitive impairment may be common in older patients with glaucoma. This has implications for treatment adherence, as difficulties in remembering information may significantly impede the ability to follow instructions from a physician. It is imperative that physicians and caregivers are aware of the prevalence of such conditions, as they are among the first to interact with such individuals. Given the high prevalence of cognitive impairment and depressive symptoms, future research should examine the impact of such factors on glaucoma treatment adherence.

Compensatory mutations restore the replication defects caused by cytotoxic T lymphocyte escape mutations in hepatitis C virus polymerase.

While human leukocyte antigen B57 (HLA-B57) is associated with the spontaneous clearance of hepatitis C virus (HCV), the mechanisms behind this control remain unclear. Immunodominant CD8(+) T cell responses against the B57-restricted epitopes comprised of residues 2629 to 2637 of nonstructural protein 5B (NS5B(2629-2637)) (KSKKTPMGF) and E2(541-549) (NTRPPLGNW) were recently shown to be crucial in the control of HCV infection. Here, we investigated whether the selection of deleterious cytotoxic T lymphocyte (CTL) escape mutations in the NS5B KSKKTPMGF epitope might impair viral replication and contribute to the B57-mediated control of HCV. Common CTL escape mutations in this epitope were identified from a cohort of 374 HCV genotype 1a-infected subjects, and their impact on HCV replication assessed using a transient HCV replicon system. We demonstrate that while escape mutations at residue 2633 (position 5) of the epitope had little or no impact on HCV replication in vitro, mutations at residue 2629 (position 1) substantially impaired replication. Notably, the deleterious mutations at position 2629 were tightly linked in vivo to upstream mutations at residue 2626, which functioned to restore the replicative defects imparted by the deleterious escape mutations. These data suggest that the selection of costly escape mutations within the immunodominant NS5B KSKKTPMGF epitope may contribute in part to the control of HCV replication in B57-positive individuals and that persistence of HCV in B57-positive individuals may involve the development of specific secondary compensatory mutations. These findings are reminiscent of the selection of deleterious CTL escape and compensatory mutations by HLA-B57 in HIV-1 infection and, thus, may suggest a common mechanism by which alleles like HLA-B57 mediate protection against these highly variable pathogens.

MHC class I chain-related protein A shedding in chronic HIV-1 infection is associated with profound NK cell dysfunction.

Natural killer (NK) cells play a critical role in host defense against viral infections. However chronic HIV-1 infection is associated with an accumulation of dysfunctional NK cells, that poorly control viral replication. The underlying mechanisms for this NK cell mediated dysfunction are not understood. Certain tumors evade NK cell mediated detection by dampening NK cell activity through the downregulation of NKG2D, via the release of soluble NKG2D-ligands, resulting in a potent suppression of NK cell function. Here we show that chronic HIV-1 infection is associated with a specific defect in NKG2D-mediated NK cell activation, due to reduced expression and transcription of NKG2D. Reduced NKG2D expression was associated with elevated levels of the soluble form of the NKG2D-ligand, MICA, in patient sera, likely released by HIV+CD4+ T cells. Thus, like tumors, HIV-1 may indirectly suppress NK cell recognition of HIV-1-infected CD4+ T cells by enhancing NKG2D-ligand secretion into the serum resulting in a profound impairment of NK cell function.

Depressive symptoms and cognitive impairment predict all-cause mortality in long-term care residents.

This study investigated whether symptoms of depression and cognitive dysfunction predicted all-cause mortality in long-term care (LTC) residents at 12 months after admission. Participants were 171 adults with a mean age of 77 in an urban LTC setting (51% African American and 49% European American). The Geriatric Depression Scale and the Dementia Rating Scale, Second Edition (DRS-2), were administered upon admission, and demographic variables and the Charlson Comorbidity Index were also recorded. Cox regression analyses found that increased depressive symptoms, lower performance on the DRS-2, and European American ethnicity were significant predictors of all-cause mortality. The overall results suggest that the combination of cognitive dysfunction and depressive symptoms can increase the chances of 12-month, all-cause mortality in LTC settings. (PsycINFO Database Record (c) 2010 APA, all rights reserved).

Malingering or expected deficits? A case of herpes simplex encephalitis.

This study describes a patient with herpes simplex encephalitis. Brain MRI showed the expected finding of medial temporal damage. Neuropsychological assessment results were consistent with the location of damage, with profound memory impairment and mildly impaired naming, but normal visuospatial and executive skills. The patient also showed a typical testing pattern of insufficient effort and possible malingering, which was concerning as she was seeking disability compensation. In spite of this, we chose to place greatest weight on the finding of deficits consistent with the type, location, and severity of brain damage, considering this to be true cognitive impairment.

Understanding of chemoprophylaxis and concordance in inflammatory bowel disease.

AIM: To assess patients' understanding for the reasons for taking 5-aminosalicylic acid or ursodeoxycholic acid as chemoprophylaxis against colorectal carcinoma associated with inflammatory bowel disease (IBD). METHODS: A questionnaire-based study using a 5-point opinion scale was performed. One hundred and ninety-two patients with colitis only and 74 patients with primary sclerosing cholangitis and IBD were invited to take part. RESULTS: Overall response rate was 58%. Sixty-four percent of patients claimed full concordance with chemoprophylaxis for maintenance of remission. Eighty-four percent of patients considered daily concordance during remission to be very important. Seventy-five percent stated they understood the reasons for taking the drugs. However, only 50% of the patients were aware of any link of their condition to bowel cancer. Seventy-nine percent of patients felt their concordance and understanding would be improved if they were informed of the chemoprophylactic potential of the medication. CONCLUSION: Despite good self-reported concordance, half of the patients were unaware of an association between colitis and bowel cancer. Explaining the potential chemoprophylactic benefits may enhance patients' overall concordance to 5-aminosalicylic acid and ursodeoxycholic acid and help maintain remission.

A systematic review of the limitations and approaches to improve detection and management of peripheral arterial disease in Hispanics.

Peripheral arterial disease (PAD) is a highly prevalent public health problem associated with major detrimental effects on quality of life and functional status, and it is also the main cause of limb amputation. More importantly, PAD has been classified as a coronary artery disease equivalent, meaning that patients with a diagnosis of PAD carry a risk for major coronary events equal to that of established coronary artery disease. PAD is also a potent predictor of stroke and death. Despite its frequent occurrence (8 to 10 million Americans are affected), little is known about the natural history of PAD in racial/ethnic minorities, particularly in Hispanics, who represent 12.5% of the United States population. Furthermore, the disease is commonly underdiagnosed and undertreated in this minority group, and outcomes are poorer in Hispanics as compared with whites. Limited access to health care, difficulties for recruitment in population-based studies, and limitations of the noninvasive screening tests are well-established barriers to determine the prevalence and natural history of PAD in Hispanics. Although the most widely used test for assessment of patients at risk for PAD is the ankle-brachial index (ABI), the test has substantial limitations in individuals with diabetes and arterial calcification, which are highly prevalent in Hispanics. The ABI should, therefore, be supplemented by the use of other noninvasive tests, such as the pulse volume recordings (PVR) and toe-brachial index. Besides the use of a combination of diagnostic techniques, the implementation of a research methodology that improves recruitment of Hispanics in population-based studies is necessary to obtain better knowledge of the epidemiology of the disease in this group. Community-based participatory research may be the most appropriate approach to study this ethnic minority because it overcomes barriers for limited access to health care and increases the possibility of overcoming distrust of research on the part of communities. Understanding the epidemiology of PAD to improve its detection and treatment among Hispanics is relevant to reduce disparities in the health status of this group, the most rapidly growing ethnic minority in the United States.

Naming test of the Neuropsychological Assessment Battery: convergent and discriminant validity.

This study investigated the convergent and discriminant validity of the naming subtest of the Neuropsychological Assessment Battery (NAB), a measure of word-finding. Seventy community-dwelling adults age 60 and above completed the NAB naming test (Forms 1 and 2), the Boston Naming Test (BNT), and other measures of verbal and visual memory, visuoperceptual skills, processing speed, and abstraction. The NAB naming test correlated highly with the BNT and with established measures of memory. The BNT correlated more strongly with education and with sex. The BNT correlated more strongly with a measure of visuoperceptual skills than the NAB naming test did, suggesting that visuoperception is more involved in the BNT. Divergent validity of the NAB naming was demonstrated by a lack of correlations with less-related measures. Findings suggest that the NAB naming test possesses convergent and divergent validity as a measure of word-finding.

Trends in workforce diversity in vascular surgery programs in the United States.

BACKGROUND: U.S. black and Hispanic populations are growing at a steady pace. In contrast, the medical profession lacks the same minority growth and representation. Women are also under-represented in many surgical disciplines. The purpose of this study was to assess trends in the proportion of women, blacks, and Hispanics admitted to vascular surgery (VS) and related specialties, and to compare them with each other and with a surgical specialty, orthopedic surgery (OS), with a formal diversity initiative. METHODS: Data on the fellowship pool of VS, interventional radiology (IR), and interventional cardiology (IC), as well as the resident pools of general surgery (GS) and orthopedic surgery (OS), were obtained from U.S. graduate medical education reports for 1999 through 2005. Cochrane-Armitage trend tests were used to assess trends in the proportion of females, blacks, and Hispanics in relation to the total physician workforce for each subspecialty. RESULTS: No significant trends in the proportion of females, blacks, or Hispanics accepted into VS and IC fellowship programs occurred during the study period. In contrast, IR, GS, and OS programs revealed significant trends for increasing proportions of at least one of the underrepresented study groups. In particular, OS, which has implemented a diversity awareness program, showed a positive trend in female and Hispanic trainees (P < .04 and P < .02, respectively). Blacks showed a significant increasing trend only in IR (P = .05). Conversely, a positive trend toward continued growth in the Hispanic group was seen in GS (P < .001), IR, and OS (P = .04 and P = .02, respectively). CONCLUSIONS: The racial/ethnic and gender composition of the physician trainee pool in vascular specialties, particularly VS, has not matched the increasing growth of underrepresented groups in the US population of patients with vascular disease. Formal programs to recruit qualified women and minorities appear successful in increasing workforce diversity.

Temporal dynamics of a predominant protease inhibitor-resistance mutation in a treatment-naive, hepatitis C virus-infected individual.

The dramatic antiviral activities of drugs that specifically inhibit hepatitis C virus replication can be tempered by baseline mutations that confer resistance. We describe the kinetics of an R155K mutation in hepatitis C virus (HCV) NS3 protease known to confer resistance to specific protease inhibitors in an individual coinfected with human immunodeficiency virus-1 and HCV. Longitudinal sequences revealed changes in the relative frequency with which this variant was observed independent of HCV replication levels, illustrating that this mutation coexists with wild-type strains in vivo in the absence of drugs. The persistence of drug-resistance mutations argues for baseline resistance genotyping at the time therapy is initiated to accurately predict the efficacy of treatment.