Added Value of Next Generation over Sanger Sequencing in Kenyan Youth with Extensive HIV-1 Drug Resistance.

HIV-1 drug resistance testing in children and adolescents in low-resource settings is both important and challenging. New (more sensitive) drug resistance testing technologies may improve clinical care, but evaluation of their added value is limited. We assessed the potential added value of using next-generation sequencing (NGS) over Sanger sequencing for detecting nucleoside reverse transcriptase inhibitor (NRTI) and nonnucleoside reverse transcriptase inhibitor (NNRTI) drug resistance mutations (DRMs). Participants included 132 treatment-experienced Kenyan children and adolescents with diverse HIV-1 subtypes and with already high levels of drug resistance detected by Sanger sequencing. We examined overall and DRM-specific resistance and its predicted impact on antiretroviral therapy and evaluated the discrepancy between Sanger sequencing and six NGS thresholds (1%, 2%, 5%, 10%, 15%, and 20%). Depending on the NGS threshold, agreement between the two technologies was 62% to 88% for any DRM, 83% to 92% for NRTI DRMs, and 73% to 94% for NNRTI DRMs, with more DRMs detected at low NGS thresholds. NGS identified 96% to 100% of DRMs detected by Sanger sequencing, while Sanger identified 83% to 99% of DRMs detected by NGS. Higher discrepancy between technologies was associated with higher DRM prevalence. Even in this resistance-saturated cohort, 12% of participants had higher, potentially clinically relevant predicted resistance detected only by NGS. These findings, in a young, vulnerable Kenyan population with diverse HIV-1 subtypes and already high resistance levels, suggest potential benefits of more sensitive NGS over existing technology. Good agreement between technologies at high NGS thresholds supports their interchangeable use; however, the significance of DRMs identified at lower thresholds to patient care should be explored further. IMPORTANCE HIV-1 drug resistance in children and adolescents remains a significant problem in countries facing the highest burden of the HIV epidemic. Surveillance of HIV-1 drug resistance in children and adolescents is an important public health strategy, particularly in resource-limited settings, and yet, it is limited due mostly to cost and infrastructure constraints. Whether newer and more sensitive next-generation sequencing (NGS) adds substantial value beyond traditional Sanger sequencing in detecting HIV-1 drug resistance in real life settings remains an open and debatable question. In this paper, we attempt to address this issue by performing a comprehensive comparison of drug resistance identified by Sanger sequencing and six NGS thresholds. We conducted this study in a well-characterized, vulnerable cohort of children and adolescents living with diverse HIV-1 subtypes in Kenya and, importantly, failing antiretroviral therapy (ART) with already extensive drug resistance. Our findings suggest a potential added value of NGS over Sanger even in this unique cohort.

What are the best endpoints for Eczema Area and Severity Index and Scoring Atopic Dermatitis in clinical practice? A prospective observational study.

BACKGROUND: Multiple strategies have been used to evaluate the minimal important change (MIC) of the Eczema Area and Severity Index (EASI) and Scoring Atopic Dermatitis (SCORAD). The meaningfulness of these MICs is not well established across all severities of atopic dermatitis (AD). OBJECTIVES: To determine the MIC of percentage and absolute improvement of EASI and SCORAD scores in adults and children with AD. METHODS: We performed a prospective dermatology practice-based study using questionnaires and evaluation by a dermatologist (n = 826). An anchor-based approach was used to determine thresholds for the percentage and absolute MICs of EASI, SCORAD and objective SCORAD (O-SCORAD) at follow-up from baseline. RESULTS: One-grade improvements of Physician's Global Assessment (PGA) and validated Investigator Global Assessment scale for AD (vIGA-AD) were associated with 50%, 35% and 35% decreases of EASI, SCORAD and O-SCORAD, respectively. The thresholds for percentage MIC of EASI (Kruskal-Wallis test, P = 0·61), SCORAD (P = 0·07) and O-SCORAD (P = 0·09) were similar across baseline AD severities. One-grade improvements of PGA and vIGA-AD were associated with 14·0- and 14·9-point decreases of EASI, 19·9- and 14·9-point decreases of SCORAD, and 15·5- and 17·4-point decreases of O-SCORAD. The thresholds for the absolute MIC of EASI (P < 0·001), SCORAD (P < 0·001) and O-SCORAD (P < 0·001) significantly differed by baseline AD severity. Percentage and absolute MICs for EASI and SCORAD were associated with improvements of AD symptoms and quality of life. CONCLUSIONS: EASI 50, SCORAD 35 and O-SCORAD 35 were meaningful percentage MICs regardless of baseline AD severity. The absolute MICs for EASI, SCORAD and O-SCORAD varied by baseline AD severity.

Measurement properties of the Rajka-Langeland severity score in children and adults with atopic dermatitis.

BACKGROUND: Multiple atopic dermatitis (AD) severity scales exist, with no gold standard for use in clinical practice. OBJECTIVES: To determine the measurement properties of the Rajka-Langeland score and compare it with other clinician-reported outcomes in adults and children with AD. METHODS: We performed a prospective dermatology practice-based study using questionnaires and evaluation by a dermatologist (n = 427). RESULTS: Rajka-Langeland had good concurrent validity with the Eczema Area and Severity Index (Spearman rho = 0·63), SCORing AD (SCORAD) (rho = 0·61), objective-SCORAD (rho = 0·52) and body surface area (rho = 0·51); good convergent validity with the numeric rating scale average-itch (rho = 0·60) and worst-itch (rho = 0·59), Patient-Oriented Eczema Measure (rho = 0·57), Dermatology Life Quality Index (rho = 0·53), Patient-Reported Outcomes Measurement Information System Itch Questionnaire (rho = 0·35-0·55) in adults and/or children; fair discriminant validity for patient- and physician-reported global AD severity; good responsiveness to change of severity of AD and itch; good reliability; internal consistency; with no floor or ceiling effects. Interpretability bands (3, clear/almost clear; 4-5, mild; 6-7, moderate; 8-9, severe) and minimal clinically important difference (1 point) were established. CONCLUSIONS: The Rajka-Langeland score showed good construct validity, reliability, internal consistency and responsiveness in adults and children with AD.

Measurement properties of the product of investigator's global assessment and body surface area in children and adults with atopic dermatitis.

BACKGROUND: Multiple clinician-reported outcome measures exist for atopic dermatitis (AD) severity. However, there is no gold standard for use in clinical practice. OBJECTIVES: To determine the measurement properties of the product of validated Investigator's Global Assessment for AD (vIGA) and body surface area (BSA) overall or divided into six categories (cBSA: 0%/0.1, <10%/10, <30%/30, <50%/50, <70%/70 and <90%/90-100%) and compare with other clinician-reported and patient-reported outcomes in adults and children with AD. METHODS: We performed a prospective dermatology practice-based study using questionnaires and evaluation by a dermatologist (n = 653). RESULTS: vIGA*BSA and vIGA*cBSA had good convergent validity with BSA (Spearman's ρ = 0.97 and 0.93), eczema area and severity index (ρ = 0.94 and 0.92), and objective SCORAD (ρ = 0.88 and 0.89); and weak-to-good convergent validity with Numeric Rating Scale average itch (ρ = 0.22 and 0.22) and worst itch (ρ = 0.27 and 0.28), Patient-Oriented Eczema Measure (ρ = 0.44 and 0.43), Dermatology Life Quality Index (ρ = 0.48 and 0.49), ItchyQOL (ρ = 0.45 and 0.46), PROMIS Sleep Disturbance (ρ = 0.46 and 0.37) and sleep-related impairment (ρ = 0.31 and 0.31) in adults and/or children; very good discriminant validity for physician-reported global AD severity; good responsiveness to change of severity of AD and itch; and good reliability (intraclass correlation coefficient [95% confidence interval]: 0.72 [0.60-0.81] and 0.74 [0.62-0.82]) with no floor or ceiling effects. Thresholds for interpretability bands and clinically important difference were established. CONCLUSIONS: vIGA*BSA and vIGA*cBSA scores showed good convergent and discriminant validity, reliability, responsiveness and interpretability in adults and children with AD, and were feasible for use in clinical practice. vIGA*BSA and vIGA*cBSA had slightly lower convergent validity than EASI or objective SCORAD, but might be more efficient to collect and score.

Measurement properties of the Patient-Reported Outcomes Information System (PROMIS® ) Itch Questionnaire: itch severity assessments in adults with atopic dermatitis.

BACKGROUND: Little is known about the validity of numeric rating scales (NRS) and verbal rating scales (VRS) for itch and itch frequency for assessing itch severity in atopic dermatitis (AD). We evaluated the Patient-Reported Outcomes Information System (PROMIS® ) Itch Questionnaire (PIQ) - itch severity assessment, including multiple NRS, VRS and frequency of itch assessments, in adults with AD and compared their performance. METHODS: Self-administered questionnaires and skin examinations were performed in 410 patients with AD (aged 18-90 years) in a dermatology practice setting. RESULTS: PIQ NRS, VRS and frequency of itch had good content validity, strong correlations with one another (Spearman correlations P < 0·001) and weak-to-moderate correlations with patient-oriented eczema measure (POEM), Eczema Area and Severity Index (EASI), objective SCORing AD (SCORAD) and Dermatology Life Quality Index (DLQI) (P < 0·001) and very good discriminant validity. Changes from baseline in NRS, VRS and frequency of itch were moderately to strongly correlated with one another, and weakly to moderately correlated with other patient-reported (POEM, SCORAD itch, DLQI) and clinician-reported outcomes (EASI, objective SCORAD). NRS and VRS worst itch and average itch showed moderate-to-good test-retest reliability. There were no floor or ceiling effects for NRS or VRS itch, but there were ceiling effects for itch frequency. Each assessment was completed in < 1 min by all patients. CONCLUSIONS: NRS, VRS and frequency of itch items from PIQ - itch severity showed good content and construct validity, reliability, and/or responsiveness in adults with AD, and were feasible for use in clinical trials and practice. What is already known about this topic? Numeric rating scales (NRS), verbal rating scales (VRS) and frequency of itch have been used to assess the burden of itch. However, there have been limited results demonstrating their validity, responsiveness, interpretability and feasibility, particularly in atopic dermatitis (AD). What does this study add? This study demonstrated that NRS, VRS and frequency of itch items from the Patient-Reported Outcomes Information System (PROMIS® ) Itch Questionnaire (PIQ) - itch severity assessments had good construct validity, responsiveness, reliability and feasibility in the assessment of adult AD. PIQ NRS, VRS and frequency of itch all appear to have sufficient validity, reliability and feasibility for use as assessments of itch in adults with AD in clinical practice and trials. What are the clinical implications of this work? PIQ NRS and VRS are all simple, valid, reliable and feasible for use in clinical practice and trials to assess itch in adults with AD. Linked Comment: Oosterhaven. Br J Dermatol 2020; 183:802-803.

Validation of Patient-Reported Outcomes Information System Sleep Disturbance and Sleep-Related Impairment in adults with atopic dermatitis.

BACKGROUND: Sleep disturbances are common in adults with atopic dermatitis (AD). Patient-Reported Outcomes Measurement Information System (PROMIS) Sleep Disturbance (SD) and Sleep-Related Impairment (SRI) are validated questionnaires to assess sleep in adults. Little is known about their measurement properties in adults with AD. OBJECTIVES: To assess the measurement properties of the PROMIS SD and SRI eight-item short forms in AD. METHODS: We performed a prospective dermatology-practice-based study using questionnaires and evaluation by a dermatologist (n = 420). RESULTS: PROMIS SD and SRI showed moderate correlations to each other (ρ = 0·67), and weak correlations with Patient-Oriented Eczema Measure (ρ = 0·43 and 0·39, respectively); average (ρ = 0·31/0·30) and worst numerical rating scale for itch (ρ = 0·32/0·30); Eczema Area and Severity Index (ρ = 0·41/0·31); and Scoring Atopic Dermatitis (SCORAD) (ρ = 0·44/0·30) (Spearman correlations, P < 0·001). PROMIS SD and SRI increased significantly and stepwise with more frequent sleep disturbance, severe itch and self-reported global AD severity (ancova, P < 0·001). PROMIS SD and SRI showed good internal consistency (Cronbach alpha 0·84 and 0·91). Changes from baseline in PROMIS SD and SRI were weakly to moderately correlated with each other and with changes of multiple patient-reported and clinician-reported AD outcomes. There were no floor or ceiling effects for PROMIS SD or SRI. The median completion time for PROMIS SD and SRI was 2 min. CONCLUSIONS: PROMIS SD and SRI showed good construct validity, internal consistency, responsiveness and feasibility to assess sleep in adult patients with AD. What is already known about this topic? The Patient-Reported Outcomes Measurement Information System (PROMIS) Sleep Disturbance (SD) and Sleep-Related Impairment (SRI) scales were found to be valid in adults with chronic disease. However, the validity and feasibility of PROMIS SD and SRI in atopic dermatitis remain unknown. What does this study add? This study demonstrated that PROMIS SD and SRI had good content, concurrent, convergent and discriminant validity; feasibility; and responsiveness, with no floor or ceiling effects observed. What are the clinical implications of this work? The PROMIS SD and SRI eight-item bank short forms appear to have sufficient validity and feasibility to be used as assessments for burden of sleep in adults with atopic dermatitis in clinical practice.

Measurement properties of three assessments of burden used in atopic dermatitis in adults.

BACKGROUND: Standardized quality-of-life (QoL) assessments can provide important and clinically relevant information. There is currently a lack of standardization in QoL assessments used in atopic dermatitis (AD). OBJECTIVES: To determine the content validity, construct validity, internal consistency, differential reporting, responsiveness, floor or ceiling effects and feasibility of the Dermatology Life Quality Index (DLQI), Itchy Quality of Life (ItchyQoL) and 5-dimensions (5-D) itch scales for assessing burden of AD in adults and to compare their performance. METHODS: Self-administered questionnaires and skin examination were performed in 340 adults with AD in a dermatology practice setting. RESULTS: DLQI, ItchyQoL and 5-D all had good content validity. DLQI, mean ItchyQoL and 5-D itch all had strong correlations with frequency of AD symptoms (Patient-Oriented Eczema Measure) and intensity of itch (numerical rating scale for itch), and moderate correlations with AD severity (Eczema Area and Severity Index and Scoring Atopic Dermatitis) (Spearman correlations, P < 0·001 for all). DLQI and 5-D itch showed good internal consistency (Cronbach's alpha = 0·89 and 0·84), although ItchyQoL appeared to have several redundant items (alpha = 0·96). Uniform and nonuniform differential item functioning by age, sex and/or race/ethnicity was found for multiple items in DLQI, ItchyQoL and 5-D itch. DLQI, ItchyQoL and 5-D itch scores all demonstrated responsiveness, although ItchyQoL demonstrated the greatest responsiveness. There were no floor or ceiling effects for total scores. The median times for completion of DLQI, ItchyQoL and 5-D itch were 2 min. CONCLUSIONS: The DLQI, ItchyQoL and 5-D itch scales all showed good content and construct validity, and responsiveness in the assessment of AD in adults, and were feasible for use in clinical trials and practice.

Validation of patient-reported global severity of atopic dermatitis in adults.

BACKGROUND: Atopic dermatitis (AD) is associated with a heterogeneous presentation and clinical course. There is a lack of simple and validated severity assessments that are feasible for clinical practice and epidemiological research. OBJECTIVES: We sought to validate patient-reported global AD severity in adults. METHODS: We performed a prospective dermatology practice-based study using questionnaires and evaluation by a dermatologist (n = 265). RESULTS: At baseline and follow-up, patient-reported global AD severity significantly correlated with oSCORAD (Spearman ρ = 0.56 and 0.49), SCORAD (0.64 and 0.56), EASI (0.56 and 0.50), BSA (0.52 and 0.45), NRS-itch (0.60 and 0.53), POEM (0.50 and 0.48), and DLQI (0.50 and 0.49) (P < .0001 for all). Patient-reported moderate and severe AD vs mild AD were associated with significantly higher oSCORAD, SCORAD, EASI, BSA, NRS-itch, POEM, and DLQI (P < .0001 for all). There was moderate concordance between patient-reported AD severity (mild, moderate, and severe) and previously developed severity strata for oSCORAD (κ = 0.39), SCORAD (κ = 0.47), EASI (κ = 0.37), NRS-itch (κ = 0.49), POEM (κ = 0.37), and DLQI (κ = 0.40). Among patients with severe disease at baseline, those who reported mild or moderate disease on follow-up had significantly greater absolute reductions of oSCORAD (-23.4/-9.7/-1.8), SCORAD (-33.0/-13.2/-2.3), EASI (-17.1/-9.8/-3.2), BSA (-46%/-15%/-4%), NRS-itch (-5/-2/0), POEM (-5/-2/0), and DLQI (-8/-6/-1) than those who continued to report severe disease (Kruskal-Wallis, P ≤ .0003 for all). CONCLUSIONS: Patient-reported AD severity appears to be sufficiently valid for assessing AD severity in the clinical and epidemiological setting.

Severity strata for five patient-reported outcomes in adults with atopic dermatitis.

BACKGROUND: Several patient-reported outcomes have been used to assess the burden of atopic dermatitis (AD). Some are disease specific, such as the Patient-Oriented Eczema Measure (POEM), while others pertain to itch, for example the numerical rating scale (NRS)-itch, ItchyQoL and 5-D itch, or dermatological disease in general, for example the Dermatology Life Quality Index (DLQI). Development of severity strata is essential for proper interpretability of these assessments. OBJECTIVES: To confirm previously developed strata for POEM, DLQI and raw ItchyQoL, and develop strata for the NRS-itch, mean ItchyQoL and 5-D itch scale for use in adults with AD. METHODS: Self-administered questionnaires were completed by 210 adults with AD in a dermatology practice setting. Strata were selected using an anchoring approach based on patient-reported disease severity. RESULTS: We confirmed the existing strata for POEM (mild 0-7, moderate 8-16, severe 17-28; κ = 0·440), DLQI (mild 0-5, moderate 6-10, severe 11-30; κ = 0·398) and NRS-itch (mild 0-3, moderate 4-6, severe 7-10; κ = 0·499). However, the preferred band for raw ItchyQoL was mild 22-58, moderate 59-74 and severe 75-110 (κ = 0·379) and for mean ItchyQoL, mild 1-2·9, moderate 3·0-3·9, severe 4·0-5·0 (κ = 0·374). The preferred band for 5-D itch scale was mild 0-11, moderate 12-17 and severe 18-25 (κ = 0·331). CONCLUSIONS: Existing strata for POEM and DLQI performed well in adult AD. Previously reported strata for visual analogue scale-itch performed best for NRS-itch. We identified banding for the raw ItchyQoL for our AD population that varies slightly from the banding published for a more heterogeneous population. Finally, we proposed strata for mean ItchyQoL and 5-D itch scale in adult AD.

Severity strata for Eczema Area and Severity Index (EASI), modified EASI, Scoring Atopic Dermatitis (SCORAD), objective SCORAD, Atopic Dermatitis Severity Index and body surface area in adolescents and adults with atopic dermatitis.

BACKGROUND: Scoring systems for assessing the signs of atopic dermatitis (AD) are complex and difficult to interpret. Severity strata are helpful to interpret these assessments properly. OBJECTIVES: To confirm previously reported strata for the Eczema Area and Severity Index (EASI), Scoring Atopic Dermatitis (SCORAD) and the objective component of SCORAD (oSCORAD), and to develop strata for the modified EASI (mEASI), Atopic Dermatitis Severity Index (ADSI) and body surface area (BSA) for use in adults with AD. METHODS: Skin examination was performed in 673 adolescents and adults (age ≥ 13 years) with diagnosed AD, in a dermatology practice setting. Strata were selected using an anchoring approach based on a four-point Investigator's Global Assessment of severity (clear of active skin lesions, mild, moderate or severe disease). RESULTS: We determined potential severity strata for EASI (0 clear, 0·1-5·9 mild, 6·0-22·9 moderate, 23·0-72 severe; κ = 0·69), mEASI (0-0·9 clear, 1-8·9 mild, 9·0-29·9 moderate, 30·0-90 severe; κ = 0·71), oSCORAD (0-7·9 clear, 8·0-23·9 mild, 24·0-37·9 moderate, 38·0-83 severe; κ = 0·70), SCORAD (0-9·9 clear, 10·0-28·9 mild, 29·0-48·9 moderate, 49·0-103 severe; κ = 0·68), ADSI (0-1·9 clear, 2-5·9 mild, 6·0-8·9 moderate, 9·0-15 severe; κ = 0·55) and BSA (0 clear, 0·1-15·9 mild, 16·0-39·9 moderate, 40·0-100 severe; κ = 0·66). oSCORAD values > 0 were found in clear skin due to the presence of xerosis, which is scored in oSCORAD. Similarly, SCORAD values > 0 were found in clear skin due to the scoring of xerosis, pruritus and sleeplessness. Similarly, mEASI and ADSI scores > 0 occurred in patients with clear skin due to scoring of pruritus. CONCLUSIONS: We recommend using these strata for interpretation of their respective measures in clinical trials of AD. There are important differences between the five assessments, which profoundly impact the interpretation of their scores.

Atopic dermatitis, atopic eczema, or eczema? A systematic review, meta-analysis, and recommendation for uniform use of 'atopic dermatitis'.

BACKGROUND: The lack of standardized nomenclature for atopic dermatitis (AD) creates unnecessary confusion for patients, healthcare providers, and researchers. It also negatively impacts accurate communication of research in the scientific literature. We sought to determine the most commonly used terms for AD. METHODS: A systematic review of the MEDLINE, EMBASE, and LILACS (1945-2016) for the terms AD, atopic eczema (AE), and multiple other eczematous disorders. RESULTS: In MEDLINE, 33 060 were identified, of which 21 299 (64.4%) publications used the term 'AD', 15 510 (46.9%) 'eczema', and only 2471 (7.5%) AE. Most of these publications used the term AD (82.0%) or eczema (70.8%) without additional nomenclature; only 1.2% used AE alone. Few publications used the terminology 'childhood eczema', 'flexural eczema', 'infantile eczema', 'atopic neurodermatitis', or 'Besnier's prurigo'. AD was rarely used until the late 1970s, after which it became the most commonly used of the three terms and continuously increased until 2015. Atopic eczema decreased between 2008 and 2015. Atopic dermatitis was the most commonly used term in studies across almost all publication types, languages, and journals. CONCLUSION: Atopic dermatitis is the most commonly used term and appears to be increasing in popularity. Given that eczema is a nonspecific term that describes the morphological appearance of several forms of dermatitis, we strongly suggest the use of a more specific term, AD, in publications, healthcare clinician training, and patient education. Support from researchers, reviewers, and editors is key to success.

HemaSpot, a Novel Blood Storage Device for HIV-1 Drug Resistance Testing.

HemaSpot, a novel dried-blood storage filter device, was used for HIV-1 pol resistance testing in 30 fresh United States blood samples and 54 previously frozen Kenyan blood samples. Genotyping succeeded in 79% and 58% of samples, respectively, improved with shorter storage and higher viral load, and had good (86%) resistance mutation concordance to plasma.

Bayesian network analysis of resistance pathways against HIV-1 protease inhibitors.

Interpretation of Human Immunodeficiency Virus 1 (HIV-1) genotypic drug resistance is still a major challenge in the follow-up of antiviral therapy in infected patients. Because of the high degree of HIV-1 natural variation, complex interactions and stochastic behaviour of evolution, the role of resistance mutations is in many cases not well understood. Using Bayesian network learning of HIV-1 sequence data from diverse subtypes (A, B, C, F and G), we could determine the specific role of many resistance mutations against the protease inhibitors (PIs) nelfinavir (NFV), indinavir (IDV), and saquinavir (SQV). Such networks visualize relationships between treatment, selection of resistance mutations and presence of polymorphisms in a graphical way. The analysis identified 30N, 88S, and 90M for nelfinavir, 90M for saquinavir, and 82A/T and 46I/L for indinavir as most probable major resistance mutations. Moreover we found striking similarities for the role of many mutations against all of these drugs. For example, for all three inhibitors, we found that the novel mutation 89I was minor and associated with mutations at positions 90 and 71. Bayesian network learning provides an autonomous method to gain insight in the role of resistance mutations and the influence of HIV-1 natural variation. We successfully applied the method to three protease inhibitors. The analysis shows differences with current knowledge especially concerning resistance development in several non-B subtypes.

Analysis of HIV-1 pol sequences using Bayesian Networks: implications for drug resistance.

Human Immunodeficiency Virus-1 (HIV-1) antiviral resistance is a major cause of antiviral therapy failure and compromises future treatment options. As a consequence, resistance testing is the standard of care. Because of the high degree of HIV-1 natural variation and complex interactions, the role of resistance mutations is in many cases insufficiently understood. We applied a probabilistic model, Bayesian networks, to analyze direct influences between protein residues and exposure to treatment in clinical HIV-1 protease sequences from diverse subtypes. We can determine the specific role of many resistance mutations against the protease inhibitor nelfinavir, and determine relationships between resistance mutations and polymorphisms. We can show for example that in addition to the well-known major mutations 90M and 30N for nelfinavir resistance, 88S should not be treated as 88D but instead considered as a major mutation and explain the subtype-dependent prevalence of the 30N resistance pathway.

Fatal liver infarction after transjugular intrahepatic portosystemic shunt procedure.

Hepatic infarction is a rare disease. We describe here a cirrhotic patient with end-stage renal failure and recurrent tense ascites with fatal hepatic infarction after transjugular intrahepatic portosystemic shunt (TIPS) procedure. Abdominal ultrasound, radionuclide liver scan, abdominal computed tomography scan, and finally liver biopsy established the diagnosis. The mechanism causing the infarct is not clear. However, as the infarct appeared after the patient had an episode of shock and disseminated intravascular coagulation, it could well be that the concomitant hepatic arterial insufficiency contributed to the infarct. Physicians should be aware of this possible catastrophic complication.

Ascending aortic pseudoaneurysm following coronary bypass in a hemodialysis patient with fever of unknown origin.

A unique patient who developed pseudoaneurysm of the ascending aorta after coronary artery bypass grafting is presented. This case is peculiar due to the presenting symptom being fever of unknown origin. It is the first description of a patient on hemodialysis, who developed ascending aortic pseudoaneurysm.

Trans-tubular potassium gradient in patients with drug-induced hyperkalemia.

BACKGROUND: Trans-tubular potassium gradient (TTKG) is considered to reflect mainly aldosterone bioactivity with regard to its kaliuretic response. We determined both TTKG and aldosterone serum concentrations in patients with severe drug-induced hyperkalemia (DIH). METHODS: Ten hyperkalemic patients with serum potassium of more than 5.5 mEq/l, and serum creatinine of less than 2.5 mg/dl (221 micromol/l) were studied prospectively. Two control groups of 10 patients each were used. Control 1 group with normal renal function, and control 2 group with normokalemia and renal failure of the same magnitude as that of the hyperkalemic patients. Serum osmolarity, electrolytes, creatinine, aldosterone and urine electrolytes and osmolarity were measured and TTKG calculated. RESULTS: DIH patients had lower TTKG values than control 1 patients (2.58 +/- 0.36 vs. 6.68 +/- 0.55, p < 0.001), and also lower than that of the control 2 patients (2.58 +/- 0.36 vs. 5.51 +/- 0.87, p < 0.01). Serum aldosterone concentration in the DIH group was higher than that of the control 1 group [24.30 +/- 5.0 vs. 7.4 +/- 2.1 pg/ml (674 +/- 139 vs. 205 +/- 58 pmol/l), p < 0.006] but not different from that of the control 2 group [24.3 +/- 5.0 vs. 15.3 +/- 3.8 pg/ml (674 +/- 139 vs. 424 +/- 106 pmol/l), respectively, p = 0.18]. Although there was some overlap in TTKG between DIH and control groups, 6 of 10 DIH patients had TTKG of less than 2.5, while none of the control patients had such a low value. CONCLUSION: DIH is characterized by lower TTKG values than those observed in patients with normal or mild-to-moderate renal failure. Other factors in addition to aldosterone seem to be involved.

Human Immunodeficiency Virus Reverse Transcriptase and Protease Sequence Database: an expanded data model integrating natural language text and sequence analysis programs.

The HIV Reverse Transcriptase and Protease Sequence Database is an on-line relational database that catalogs evolutionary and drug-related sequence variation in the human immunodeficiency virus (HIV) reverse transcriptase (RT) and protease enzymes, the molecular targets of anti-HIV therapy (http://hivdb.stanford.edu). The database contains a compilation of nearly all published HIV RT and protease sequences, including submissions from International Collaboration databases and sequences published in journal articles. Sequences are linked to data about the source of the sequence sample and the antiretroviral drug treatment history of the individual from whom the isolate was obtained. During the past year 3500 sequences have been added and the data model has been expanded to include drug susceptibility data on sequenced isolates. Database content has also been integrated with didactic text and the output of two sequence analysis programs.