Predictors of disability in a childhood-onset systemic lupus erythematosus cohort: results from the CARRA Legacy Registry.

Objective Few descriptions of physical disability in childhood-onset SLE (cSLE) exist. We sought to describe disability in a large North American cohort of patients with cSLE and identify predictors of disability. Methods Sociodemographic and clinical data were obtained from the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Legacy Registry for patients with cSLE enrolled between May 2010 and October 2014. The Childhood Health Assessment Questionnaire (CHAQ) was used to assess disability and physical functioning. Chi-square tests were used for univariate analyses, and multivariate logistic regression was used to assess predictors of disability. Results We analyzed data for 939 patients with cSLE. The median and mean CHAQ scores were 0 and 0.25, respectively, and 41% of the cohort had at least mild disability. Arthritis and higher pain scores were significantly associated with disability as compared to those without disability ( p < 0.001). In multivariate logistic regression analysis, low annual income, arthritis, and higher pain scores were associated with disability at baseline. Conclusions Disability as measured by baseline CHAQ was fairly common in cSLE patients in the CARRA Legacy Registry, and was associated with low household income, arthritis, and higher pain scores. In addition to optimal disease control, ensuring psychosocial supports and addressing pain may reduce disability in cSLE. Further study is needed of disability in cSLE.

Targeted next generation sequencing reveals a common genetic pathway for colorectal cancers with chromosomal instability and those with microsatellite and chromosome stability.

INTRODUCTION: Microsatellite stable sporadic colorectal cancers (CRCs) can be classified as either tumours with chromosomal instability (CIN+) or tumours that are 'Microsatellite and Chromosomal Stable' (MACS). The CIN + tumours are aneuploid whilst MACS are near-diploid; little else is known about their differences. We compared the mutation profiles of CIN + and MACS CRCs. METHOD: Targeted Next Generation Sequencing for mutation in 26 driver genes (TruSight-26 kit) was undertaken in 46 CIN + and 35 MACSCRCs. Tumours were compared for mutation frequency, allelic imbalance and clonal heterogeneity. RESULTS: Mutations were detected in 58% genes and, overall, mutation in driver genes was at expected frequencies. Comparison of classes revealed similar mutation frequencies in most genes and allelic imbalance atAPC and TP53. Differences were seen in mutation frequency in KRAS (41% CIN+ vs 68% MACS, p = 0.015) and GNAS (0% CIN+ vs 12% MACS, p = 0.032). Twenty percent CIN + CRCs harboured mutations only in TP53 - a profile not seen in the MACS tumours (p = 0.009). None of the differences were significant after multiple testing corrections. CONCLUSIONS: The mutation profiles of CIN and MACS CRCs are similar. The events allowing aneuploidy (or forcing retention of diploidy) remain unknown.

Targeted Next-Generation Sequencing Validates the Use of Diagnostic Biopsies as a Suitable Alternative to Resection Material for Mutation Screening in Colorectal Cancer.

BACKGROUND: Mutation testing in the context of neoadjuvant therapy must be performed on biopsy samples. Given the issue of tumour heterogeneity, this raises the question of whether the biopsies are representative of the whole tumour. Here we have compared the mutation profiles of colorectal biopsies with their matched resection specimens. METHODS: We performed next-generation sequencing (NGS) analysis on 25 paired formalin-fixed, paraffin-embedded colorectal cancer biopsy and primary resection samples. DNA was extracted and analysed using the TruSight tumour kit, allowing the interrogation of 26 cancer driver genes. Samples were run on an Illumina MiSeq. Mutations were validated using quick-multiplex-consensus (QMC)-polymerase chain reaction (PCR) in conjunction with high resolution melting (HRM). The paired biopsy and resection tumour samples were assessed for presence or absence of mutations, mutant allele frequency ratios, and allelic imbalance status. RESULTS: A total of 81 mutations were detected, in ten of the 26 genes in the TruSight kit. Two of the 25 paired cases were wild-type across all genes. The mutational profiles, allelic imbalance status, and mutant allele frequency ratios of the paired biopsy and resection samples were highly concordant (88.75-98.85%), with all but three (3.7%) of the mutations identified in the resection specimens also being present in the biopsy specimens. All 81 mutations were confirmed by QMC-PCR and HRM analysis, although four low-level mutations required a co-amplification at lower denaturation temperature (COLD)-PCR protocol to enrich for the mutant alleles. CONCLUSIONS: Diagnostic biopsies are adequate and reliable materials for molecular testing by NGS. The use of biopsies for molecular screening will enhance targeted neoadjuvant therapy.

N_LyST: a simple and rapid screening test for Lynch syndrome.

AIMS: We sought to use PCR followed by high-resolution melting analysis to develop a single closed-tube screening panel to screen for Lynch syndrome. This comprises tests for microsatellite instability (MSI), MLH1 methylation promoter and BRAF mutation. METHODS: For MSI testing, five mononucleotide markers (BAT25, BAT26, BCAT25, MYB, EWSR1) were developed. In addition, primers were designed to interrogate Region C of the MLH1 promoter for methylation (using bisulphite-modified DNA) and to test for mutations in codon 600 of BRAF. Two separate cohorts from Nottingham (n=99, 46 with MSI, 53 being microsatellite stable (MSS)) and Edinburgh (n=88, 45 MSI, 43 MSS) were tested. RESULTS: All the cases (n=187) were blind tested for MSI and all were correctly characterised by our panel. The MLH1 promoter and BRAF were tested only in the Nottingham cohort. Successful blinded analysis was performed on the MLH1 promoter in 97 cases. All MSS cases showed a pattern of non-methylation while 41/44 cases with MSI showed full methylation. The three cases with MSI and a non-methylated pattern had aberrations in MSH2 and MSH6 expression. BRAF mutation was detected in 61% of MSI cases and 11% of MSS cases.Finally, 12 cases were blind screened by using the whole panel as a single test. Of these, five were identified as MSS, four as MSI/non-LS and three as MSI/possible LS. These results were concordant with the previous data. CONCLUSION: We describe the Nottingham Lynch Syndrome Test (N_LyST). This is a quick, simple and cheap method for screening for Lynch syndrome.

Controversies in tuberculous infection among pediatric infectious disease specialists in North America.

OBJECTIVE: To evaluate the extent to which advancements in the diagnosis and treatment of latent tuberculous infection (LTBI) have been integrated into practice by pediatric infectious disease (PID) specialists. DESIGN: We conducted an online survey of the Infectious Diseases Society of America's Emerging Infections Network (EIN) membership. RESULTS: Of the 323 members, 197 (61%) responded: 7% cared for ⩾5 children with TB disease and 34% for ⩾5 children with LTBI annually. We identified substantial variations in the use of interferon-gamma release assays (IGRAs) based upon age, immune status, and TB risk factors. In addition, tuberculin skin test (TST) use was three times more common in younger children. Variations existed in managing children with discordant TST and IGRA results. Less variation existed in LTBI treatment, with 86% preferring a 9-month course of isoniazid; few other, newer regimens were used routinely. CONCLUSION: Substantial variations exist in LTBI management; uptake of newer diagnostic tools and treatment regimens has been slow. Variations in practice and the lag time to integrating new data into practice may indicate the relative infrequency with which providers encounter LTBI. Our findings reflect the need for increased visibility of existing TB guidelines and resources for expert consultation for scenarios not covered by guidelines.

Pneumocystis carinii pneumonia prophylaxis and early clinical manifestations of severe perinatal human immunodeficiency virus type 1 infection. Northern California Pediatric HIV Consortium.

BACKGROUND: Some children with perinatal HIV infection develop early progression to severe symptoms (Category C) within the first 4 years of life. Prophylactic therapy with trimethoprim-sulfamethoxazole (TMP/SMX) may affect progression by decreasing the incidence of Pneumocystis carinii pneumonia (PCP). METHODS: HIV progression to Category C in the first 3 years of life was retrospectively analyzed in a population-based cohort of children with perinatal HIV infection followed for > or = 3 years from birth. Time to development of Category C and clinical patterns of new Category C diagnoses were examined in relation to patterns of PCP prophylaxis before diagnosis. RESULTS: Fifty-eight of 147 children developed 67 initial category C diseases by 3 years of age: PCP (n=24), encephalopathy (n=22), other opportunistic infections (n=19) and wasting (n=2). Before diagnosis therapy included TMP/ SMX and zidovudine (ZDV) (n=11), TMP/SMX alone (n=7), ZDV alone (n=1) and neither (n= 39). The probability of developing a Category C diagnosis after 2 years was significantly lower among children who received TMP/SMX compared with those who did not (29%, TMP/SMX vs. 45%, no TMP/SMX; 30%, TMP and ZDV vs. 45%, no therapy; P < 0.01). The frequency of PCP was significantly lower and that of HIV encephalopathy was significantly higher among children receiving TMP/SMX +/- ZDV before Category C diagnosis than among children receiving neither. CONCLUSION: In this study PCP prophylaxis was associated with longer time to Category C diagnoses in the first 3 years of life. This association was related to a decreased incidence of PCP and an increased incidence of encephalopathy as the first Category C diagnosis among children who received TMP/SMX.

A cost-effectiveness analysis of universal versus selective immunization with Mycobacterium bovis bacille Calmette-Guérin in Finland.

SETTING: Mycobacterium bovis bacille Calmette-Guerin (BCG) is provided to all infants born in Finland. OBJECTIVE: To analyze the cost-effectiveness of universal versus selective BCG immunization. DESIGN: A Markov model was developed to simulate rates of tuberculosis (TB) and non-tuberculous mycobacterial disease (NTM), and to examine the cost-effectiveness in terms of cost per case averted of three different strategies: universal BCG, selective BCG (10% of infants at higher TB risk than other infants) or no BCG immunization. RESULTS: In a cohort of 60,000 infants over 15 years, the model predicts five cases each of TB and NTM disease with universal immunization, 8-21 TB and 31 NTM cases with various strategies of selective immunization, and 25 TB and 34 NTM cases with no BCG immunization. BCG side-effects are predicted in 5, 0.5 and 0 infants, respectively. The cost per case averted for immunization strategies ranges from a cost of 38,311 US dollars to a savings of 323 dollars as selective immunization becomes more efficient at targeting infants at highest risk of TB. CONCLUSIONS: In a country with a low incidence of pediatric tuberculosis, selective BCG immunization is a more cost-effective strategy than universal BCG immunization for the prevention of tuberculosis, but results in an increase in NTM cases.

Estimating the population impact of an intervention: a decision-analytic approach.

The aim of this paper is to highlight the role for decision analysis in assessing outcomes of medical interventions at a population level. The basic steps of decision analysis are introduced and an illustrative hypothetical preventive intervention is examined. Specific modelling challenges that arise when estimating the population impact of an intervention are described and each is accompanied by an example. Decision analysis can provide useful information for health policy decision makers by identifying the intervention(s) with the largest beneficial impact on health over a wide range of assumptions. In addition, by focusing attention on the parameters with the greatest influence on projected outcomes, decision analysis can aid in identifying critical areas for future research.

A computerized school-based health assessment with rapid feedback to improve adolescent health.

Adolescent health problems are often undetected in physicians' offices. The Dartmouth Primary Care Cooperative Information Project has developed a validated and reliable approach to identify adolescent health problems and initiate education in a school setting. A self-administered, anonymous, 26-item questionnaire was given to 204 students in a rural high school. Responses were scanned into PC-based software. Within one working day students were given individualized letters identifying their problem health issues as detected by the questionnaire and recommendations for education. Ninety-nine percent of students participated. Six weeks later 49% of a sample of 41 students reported reading the information and 50% planned to change behavior. This standardized, validated strategy of adolescent health assessment, feedback, and education was feasible for use in schools. The school responded to the data by employing a psychologist to address mental health needs.

Acute myocardial infarction mortality in VA versus non-VA settings.

Mortality associated with acute myocardial infarction has declined steadily over the past 25 years. This study was conducted to compare in-hospital mortality among men treated in VA versus non-VA settings. Results supported declines in mortality since 1980 to an overall rate of 11%, as reported in published literature and found in the VA data base. Mortality among men treated in VA settings mirrored rates reported for non-VA settings, both overall and by age groups. Findings were shared with VA Medical Centers for use in identifying opportunities to improve clinical practice.

The geriatric foot: disorders and treatment.

The geriatric population is steadily increasing; their foot disorders require special expertise. Conservative and surgical management are discussed.

Preparation of mental health personnel for the delivery of mental retardation services.

The developmental experience of an urban community mental health-mental retardation center is presented as a guiding model for other community mental health centers interested in "tooling up" their mental retardation services. Surveying personnel needs, establishing educational objectives tailored to personnel, presenting specific knowledge about mental retardation, clarifying mandates for community mental health-mental retardation service, and two conceptual frameworks for service delivery are elaborated.

The intraosseous blood supply of the fifth metatarsal: implications for proximal fracture healing.

Fractures of the proximal fifth metatarsal can be divided into two distinct groups based on anatomical location and clinical course. Fractures of the tuberosity often heal well with nonoperative treatment, whereas fractures occurring in the proximal diaphysis (up to 1.5 cm distal to the tuberosity) have significantly increased risk for delayed union or nonunion. It is the purpose of this paper to describe the intraosseous vascular anatomy of the fifth metatarsal, and the clinical implications for basilar fracture healing. Ten fresh-frozen amputation or cadaver specimens were studied following arterial injection with India ink or barium sulfate suspension. The intraosseous blood supply to the fifth metatarsal tuberosity arose from numerous metaphyseal vessels penetrating the nonarticular surfaces of the tuberosity in a random, radiate pattern. The blood supply to the proximal diaphysis was derived primarily from the nutrient artery, which gave rise to longitudinal intramedullary branches. The arterial supply to the tuberosity joined the supply of the proximal diaphysis in the area just distal to the tuberosity, corresponding to the region of poor prognosis for fracture healing. This suggests that a relative lack of blood supply following a proximal diaphyseal fracture may contribute to delayed union and nonunion.

A comparison of nonweight-bearing and weight-bearing radiographs of the foot.

This study compares the standardized measurements of the foot in nonweight-bearing and weight-bearing radiographs. Both normal and hallux valgus patients were studied. The results show that some changes thought to occur with weight-bearing cannot be consistently demonstrated. Obtaining both weight-bearing and nonweight-bearing views may not be routinely indicated in all patients.

Effect of hydrochlorothiazide on the pharmacokinetics of enalapril in hypertensive patients with varying renal function.

An open, randomised, cross-over study was performed to investigate the pharmacokinetics of enalaprilat, administered as 20 mg enalapril both as monotherapy and in combination with hydrochlorothiazide (HCTZ 12.5 mg). Three groups of 6 hypertensive patients were enrolled [untreated diastolic blood pressure (DBP) 90-115 mm Hg]; normal renal function [glomerular filtration rate (GFR) > 81 ml min-1 1.73 m-2], mild renal impairment (GFR 51-80 ml min-1 1.73 m-2), and moderate renal impairment (GFR 31-50 ml min-1 1.73 m-2). The pharmacokinetics of enalaprilat and enalaprilat plus HCTZ correlated predictably with renal impairment with increased plasma concentrations and decreased urinary elimination at lower values of GFR. The coadministration of HCTZ had no significant effect on the pharmacokinetics of enalaprilat in any group. We conclude that although the pharmacokinetics of both enalaprilat and HCTZ are related to renal function, HCTZ has no significant effect on the pharmacokinetics of enalaprilat and that dosage adjustment for both regimens should be based on renal function.

Posterior heel pain associated with a calcaneal step and Achilles tendon calcification.

Factors are examined which may be associated with chronic posterior heel pain of nonrheumatologic and nonmetabolic etiology. The charts of patients in whom Haglund's disease retrocalcaneal bursitis, or "pump bumps" was diagnosed during the period from 1963-1978 at The Hospital for Special Surgery, were reviewed. Nineteen patients met the criteria of symptomatic patients. The radiographs in 12 of these patients were available for review. These cases and 104 control cases were evaluated for the presence of calcaneal spurs, Achilles tendon calcifications and a posterior calcaneal step. In addition, Fowler-Philip measurements were obtained from the radiographs and compared with Fowler and Philip's results. Although the Fowler-Philip angles of the two groups were not significantly different (p greater than 0.05), the symptomatic heels had a significantly longer horizontal calcaneal length (p less than 0.05). The incidences of Achilles tendon calcification (p = 0.004) and of a posterior calcaneal step (p less than 0.001) were higher in patients who had chronic posterior heel pain as compared to a control population. An increased horizontal length of the calcaneus and the presence of a posterior calcaneal step appeared to cause chronic posterior heel pain and degenerative lesions of the Achilles tendon. Although a posterosuperior calcaneal prominence is theoretically important, it was not in this series. A posterior calcaneal step may alter the tension within the tendon, resulting in microscopic tendon injury, decreased vascularity and loss of strength, with subsequent calcification or rupture.