Medial arterial calcification in the feet of diabetic patients and matched non-diabetic control subjects

Summary The prevalence and distribution of medial arterial calcification was assessed in the feet of four subject groups; 54 neuropathic diabetic patients with previous foot ulceration (U), median age 60.5 (50.5–67 interquartile range) years, duration of diabetes 19.5 (9.9–29.9) years; 40 neuropathic diabetic patients without a foot ulcer history (N), age 68 (62–73) years, duration of diabetes 14.0 (8.0–28.0) years; 43 non-neuropathic diabetic patients (NN), age 60.5 (52–68.5) years, duration of diabetes 14.0 (8.0–28.0) years and 50 non-diabetic control subjects, age 62.5 (53.7–70) years. A single radiologist graded medial arterial calcification as absent, mild or severe, at the ankle, hind-foot, mid-foot, metatarsals and toes on standardised plain lateral and antero-posterior foot radiographs taken by a single radiographer. Diabetes history, vibration perception threshold, ankle systolic pressure and serum creatinine were also assessed. Medial arterial calcification was significantly greater (total score 18 [3–31]) in neuropathic diabetic patients with previous ulceration (U vs N p<0.01, U vs NN p<0.001). Non-neuropathic diabetic patients did not have significantly higher arterial calcification scores than age-matched non-diabetic control subjects. Medial arterial calcification correlated with vibration perception threshold (r=0.35), duration of diabetes (r=0.32) and serum creatinine (r=0.41), (all p<0.01). Logistic regression models showed vibration perception and duration of diabetes to predict the probability of any calcification. Serum creatinine level was added to predict severe calcification. Ordered categorical modelling confirmed that medial arterial calcification was significantly heavier at the ankle than the toes for all groups, odds ratio 4.35 (2.94–6.43, 95% confidence intervals), (p<0.01). Ankle systolic pressure and ankle-brachial pressure index were significantly associated with degree of arterial calcification, r=0.40 and r=0.35, respectively, (both p<0.01) in diabetic patients. However, arterial calcification was present in more than one-third of patients with an ankle-brachial pressure index of less than 1.0. In conclusion, although ankle pressures correlate with the degree of arterial calcification, medial arterial calcification may be present in patients with low ankle systolic pressures, which may be falsely elevated even at normal values. This finding may provide a rationale for the use of toe rather than ankle pressure measurements in diabetic patients, particularly those with peripheral neuropathy, and this hypothesis should be directly tested in future studies.     

Physician awareness of alcohol use disorders among older patients

OBJECTIVES: To determine primary care physicians’ awareness of, and screening practices for, alcohol use disorders (AUDs) among older patients. DESIGN: Cross-sectional telephone survey of a national sample of primary care physicians. PARTICIPANTS: Physicians randomly sampled from the Masterfile database of the American Medical Association and stratified by specialty as family practice physicians, internal medicine physicians, and either family practice or internal medicine physicians with geriatric certification. MAIN RESULTS: A total of 171 physicians were contacted: 155 (91%) agreed to participate, and responses were analyzed from 150 (50 family practice, 50 internal medicine, 50 with geriatric certification). The median prevalence estimate of AUDs among older patients was 5% for each group of physicians. In contrast to published prevalence rates of AUDs ranging from 5% to 23%, 38% of physicians reported prevalence estimates of less than 5%, and 5% cited estimates of at least 25%. Compared with the other groups, the physicians with geriatric certification were more likely to report no regular screening (42% vs 20% for family practice vs 18% for internal medicine, p=.01), while younger (<40 years) and middle-aged physicians (40–55 years) reported higher annual screening rates relative to older physicians (>55 years) (77% vs 60% vs 44% respectively, p=.03). Among physicians who regularly screened (n=110), 100% asked quantity-frequency questions, 39% also used the CAGE questions, and 15% also cited use of biochemical markers. CONCLUSIONS: Primary care physicians may “underdetect” AUDs among older patients. The development of age-specific screening methods and physician education may facilitate detection of older patients with (or at risk for) these disorders.     

Screening for problem drinking

OBJECTIVE: To compare self-administered versions of three questionnaires for detecting heavy and problem drinking: the CAGE, the Alcohol Use Disorders Identification Test (AUDIT), and an augmented version of the CAGE. DESIGN: Cross-sectional surveys. SETTING: Three Department of Veterans Affairs general medical clinics. PATIENTS: Random sample of consenting male outpatients who consumed at least 5 drinks over the past year (“drinkers”). Heavy drinkers were oversampled. MEASUREMENTS: An augmented version of the CAGE was included in a questionnaire mailed to all patients. The AUDIT was subsequently mailed to “drinkers.” Comparison standards, based on the tri-level World Health Organization alcohol consumption interview and the Diagnostic Interview Schedule, included heavy drinking (>14 drinks per week typically or ≥5 drinks per day at least monthly) and active DSM-IIIR alcohol abuse or dependence (positive diagnosis and at least one alcohol-related symptom in the past year). Areas under receiver operating characteristic curves (AUROCs) were used to compare screening questionnaires. MAIN RESULTS: Of 393 eligible patients, 261 (66%) returned the AUDIT and completed interviews. For detection of active alcohol abuse or dependence, the CAGE augmented with three more questions (AUROC 0.871) performed better than either the CAGE alone or AUDIT (AUROCs 0.820 and 0.777, respectively). For identification of heavy-drinking patients, however, the AUDIT performed best (AUROC 0.870). To identify both heavy drinking and active alcohol abuse or dependence, the augmented CAGE and AUDIT both performed well, but the AUDIT was superior (AUROC 0.861). CONCLUSIONS: For identification of patients with heavy drinking or active alcohol abuse or dependence, the self-administered AUDIT was superior to the CAGE in this population. This research was supported by Department of Veteran Affairs, Hines Center for Cooperative Studies in Health Services Research, grant 91-007, and Health Services Research and Development, grant SDR 96-002, Ambulatory Care Quality Improvement Project (ACQUIP); a grant from the University of Washington Alcohol and Drug Abuse Institute; and the Health Services Research and Development Field Program and Medical Service, Seattle Division, VA Pudget Sound Health Care System.     

Utilization of papanicolaou smears by South Asian women living in the United States

OBJECTIVES: Papanicolaou (Pap) smears are an underutilized screening modality among racial and ethnic minorities. However, no data exist on Pap smear utilization among South Asians, a rapidly growing population in the United States, whose country of origin includes India, Pakistan, Bangladesh, and Sri Lanka. We determined rates and identified variables associated with Pap smear receipt by South Asians. DESIGN: A self-administered survey instrument was mailed to a random sample of South Asians nationwide over a 3-month time period. South Asian households were identified by surnames that were used to search white pages in telephone directories, Department of Motor Vehicle records, and voter registries. Questions regarding Pap smear receipt were taken from the 1999 National Health Interview Survey. Sociodemographic information and measures of acculturation were obtained. PARTICIPANTS: A nationwide nonprobability sample of South Asian women. INTERVENTION: Cross-sectional observational study. MEASUREMENTS AND MAIN RESULTS: The overall response rate was 42%. In this sample, South Asians belonged to a high socioeconomic strata (SES), with 45% having a household income of >$80,000 and 42% having a master's degree. Three quarters of the respondents (73%) reported having a Pap smear in the last 3 years. In multivariate logistic regression analysis, South Asian women had greater odds of having had a Pap smear if they were married (P <.001), more educated (P =.004), had a usual source of care (P =.002), and were more acculturated (P =.004). CONCLUSIONS: Despite the high SES of South Asian women, their rates of Pap smear receipt were lower than national recommendations. Marital status, socioeconomic status, and acculturation are all associated with Pap smear receipt. South Asian communities should be targeted for outreach to promote Pap smear utilization.     

Is the distal hyperplastic polyp a marker for proximal neoplasia?

CONTEXT: The current literature is unclear about the association between distal hyperplastic polyps and synchronous neoplasia (adenomatous polyps and cancer) in the proximal colon. OBJECTIVE: To estimate the prevalence of proximal neoplasia associated with distal hyperplastic polyps. DATA SOURCES: Database searches (medline and embase from 1966 to 2001) and manual search of the bibliographies of included and excluded studies, case reports, editorials, review articles, and textbooks of Gastroenterology. STUDY SELECTION: Studies describing the prevalence of proximal neoplasia in persons with distal hyperplastic polyps. DATA EXTRACTION: Demographics, clinical variables, study design, and prevalence of proximal neoplasia associated with various distal colorectal findings. DATA SYNTHESIS: Of 18 included studies, 12 involved asymptomatic individuals in which the pooled absolute risk of any proximal neoplasia associated with distal hyperplastic polyps was 25% (95% confidence interval [95% CI], 21% to 29%). In 4 studies where colonoscopy was performed irrespective of distal findings, the absolute risk was 21% (95% CI, 14% to 28%). The relative risk of finding any proximal neoplasia in persons with distal hyperplastic polyps was 1.3 (95% CI, 0.9 to 1.8) compared to those with no distal polyps. Among 6 studies of patients with symptoms or risk factors for neoplasia, the absolute risk of proximal neoplasia was 35% (95% CI, 32% to 39%) in persons with distal hyperplastic polyps. In 2 studies of screening colonoscopy, advanced proximal neoplasia (cancer, or a polyp with villous histology or severe dysplasia, or a tubular adenoma >/=1 cm) was present in 4% to 5% of persons with distal hyperplastic polyps, which was 1.5 to 2.6 times greater than in those with no distal polyps. CONCLUSIONS: In asymptomatic persons, a distal hyperplastic polyp is associated with a 21% to 25% risk for any proximal neoplasia and a 4% to 5% risk of advanced proximal neoplasia, and may justify examination of the proximal colon. Further study is needed to determine the risk of advanced proximal neoplasia associated with size and number of distal hyperplastic polyps.     

A decision analysis of surveillance for colorectal cancer in ulcerative colitis

BACKGROUND: Patients with long standing, extensive ulcerative colitis have an increased risk of developing colorectal cancer. AIMS: To assess the feasibility of surveillance colonoscopy in preventing death from colorectal cancer. PATIENTS: A hypothetical cohort of patients with chronic ulcerative colitis. METHODS: The benefits of life years saved were weighted against the costs of biannual colonoscopy and proctocolectomy, and the terminal care of patients dying from colorectal cancer. Two separate Markov processes were modelled to compare the cost-benefit relation in patients with or without surveillance. The cumulative probability of developing colorectal cancer served as a threshold to determine which of the two management strategies is associated with a larger net benefit. RESULTS: If the cumulative probability of colorectal cancer exceeds a threshold value of 27%, surveillance becomes more beneficial than no surveillance. The threshold is only slightly smaller than the actual cumulative cancer rate of 30%. Variations of the assumptions built into the model can raise the threshold above or lower it far below the actual rate. If several of the assumptions are varied jointly, even small changes can lead to extreme threshold values. CONCLUSIONS: It is not possible to prove that frequent colonoscopies scheduled at regular intervals are an effective means to manage the increased risk of colorectal cancer associated with ulcerative colitis.     

SPA免疫便潜血试验和直肠粘液T抗原试验互补普查大肠癌及其随访

本文联合采用人血红蛋白抗血清包被的含A蛋白葡萄球菌(SPA)进行免疫便潜血试验(SPA试验)和直肠粘液T抗原检测(T抗原试验)用于大肠癌普查初筛并对筛检人群进行随访。结果表明,在4843例无症状人群中,SPA和T抗原试验阳性者分别为472例(9.75％)和297例(6.13％).共769例阳性者行纤维结肠镜检查,检出大肠癌4例,腺瘤48例(>1.0cm者17例,占35.4％)。其中,SPA试验中仅3例癌,29例腺瘤阳性,T抗原试验中2例癌,27例腺瘤阳性,提示联合这两种初筛试验可提高大肠癌及其腺瘤的检出率。为验证普查后减少大肠肿瘤发生的效果,2年后对这些人群采用同样的普查方案随访,结果在受检的3641例人群中,共477例阳性者行纤维结肠镜检查,未发现大肠癌病例,腺瘤18例(>1.0cm者仅4例,占22.2％)。将两次检出的腺瘤进行不典型增生程度的比较,第二次检出的腺瘤轻度不典型增生病变占88.89％(16例),中重度不典型增生病变仅占11.11％(2例),而第一次检出腺瘤、中重度不典型增生病变占25％(12例)。上述结果表明利用这两种初筛试验进行互补性普查。可提高大肠癌及癌前病变的检出率,随访结果提示在无症状人群普查,不仅可使大肠癌及腺瘤的再检出率明显减少,且可使中重度不典型增生病变的发病机会明显减少。     

Multiplexed barcoded CRISPR-Cas9 screening enabled by CombiGEM

The orchestrated action of genes controls complex biological phenotypes, yet the systematic discovery of gene and drug combinations that modulate these phenotypes in human cells is labor intensive and challenging to scale. Here, we created a platform for the massively parallel screening of barcoded combinatorial gene perturbations in human cells and translated these hits into effective drug combinations. This technology leverages the simplicity of the CRISPR-Cas9 system for multiplexed targeting of specific genomic loci and the versatility of combinatorial genetics en masse (CombiGEM) to rapidly assemble barcoded combinatorial genetic libraries that can be tracked with high-throughput sequencing. We applied CombiGEM-CRISPR to create a library of 23,409 barcoded dual guide-RNA (gRNA) combinations and then perform a high-throughput pooled screen to identify gene pairs that inhibited ovarian cancer cell growth when they were targeted. We validated the growth-inhibiting effects of specific gene sets, including epigenetic regulators KDM4C/BRD4 and KDM6B/BRD4, via individual assays with CRISPR-Cas–based knockouts and RNA-interference–based knockdowns. We also tested small-molecule drug pairs directed against our pairwise hits and showed that they exerted synergistic antiproliferative effects against ovarian cancer cells. We envision that the CombiGEM-CRISPR platform will be applicable to a broad range of biological settings and will accelerate the systematic identification of genetic combinations and their translation into novel drug combinations that modulate complex human disease phenotypes.New therapeutic strategies are needed to treat complex human diseases. Because disease phenotypes are often regulated by interwoven genetic networks, exploiting combination therapy to target multiple pathways, as opposed to only single ones, can enhance treatment efficacy (1). However, discovering effective combination therapies for human diseases is challenging with existing methods, due to the cost, effort, and labor required to construct and analyze each combination (2). For example, the National Cancer Institute tested ∼5,000 pairwise combinations of 100 cancer drugs against the NCI-60 panel in a study that took 2 y and cost about USD $4 million (3). Thus, there is a need for technological advances to accelerate the identification of effective combinatorial therapies. Here, we used our combinatorial genetics en masse (CombiGEM)-CRISPR platform to perform rapid pooled screening of pairwise genetic knockouts against genes coding for epigenetic regulators and then translated our screen hits into drug combinations against human ovarian cancer cells.CRISPR-Cas9 technology has been used for large-scale genetic perturbation screens with single-guide RNA (sgRNA) libraries for gene knockouts (4–7), repression, and activation (8, 9). Despite its simplicity for multiplexed genetic perturbations (10–12), new methods are needed to enable high-throughput CRISPR-Cas9–based screening with combinatorial sets of guide RNAs (gRNAs), which would be broadly useful for studying combinatorial gene functions in multigenic phenotypes and diseases. By using CombiGEM-based DNA assembly (13, 14), we developed a strategy for the simple and efficient assembly of barcoded combinatorial gRNA libraries. These libraries can be delivered into human cells by lentiviruses to create genetically ultradiverse cell populations harboring unique gRNA combinations that can be tracked via barcode sequencing in pooled assays. This strategy, termed CombiGEM-CRISPR, uses one-pot cloning steps to enable the assembly of combinatorial gRNA libraries, thus simplifying and accelerating the workflow toward systematic analysis of combinatorial gene functions.     

2006-2012年西安市新生儿疾病筛查情况分析

目的 分析西安市2006-2012年先天性甲状腺功能低下症(congenital hypothyroidism, CH)和苯丙酮尿症(phenylketonuria, PKU)筛查情况、发病率及召回率。方法 采用回顾性分析方法, 应用时间分辨免疫荧光法和免疫荧光法分别测定Tsh和Phe浓度。结果 西安市新生儿疾病筛查中心2006-2012年共筛查新生儿384 336例, 筛查出CH 263例, 发病率1∶1 461, PKU 153例, 发病率1∶2 512 。2006年至2012年筛查人数由20 008例上升到86 375例, CH阳性检出率由1∶6 669升高至1∶1 464, PKU阳性检出率由1∶5 002升至1∶2 399, 筛查率从40.41%上升至85.16%, 召回率从70.7%提高至96.0%, 阳性率、筛查率和召回率都在逐年上升。结论 CH、PKU可以通过新生儿早期筛查, 早发现、早诊断、早治疗, 避免智力和体格发育低下以及其他器官功能的损害, 提高出生人口素质, 避免给社会和家庭带来的沉重负担, 是降低出生缺陷发生率的有效措施。     

Targeted Melanoma Prevention Intervention: A Cluster Randomized Controlled Trial

PURPOSE

Targeted interventions to reduce the risk and increase the early detection of melanoma have the potential to save lives. We aimed to assess the effect of such an intervention on patient prevention behavior.

METHODS

We conducted a pilot clustered randomized controlled trial, comparing a targeted screening and education intervention with a conventional information-based campaign in 20 private surgeries in western France. In the intervention group, 10 general practitioners identified patients at elevated risk for melanoma with a validated assessment tool, the Self-Assessment Melanoma Risk Score (SAMScore), examined their skin, and counseled them using information leaflets. In the control group, 10 general practitioners displayed a poster and the leaflets in their waiting room and examined patients’ skin at their own discretion. The main outcome measures were sunbathing and skin self-examinations among patients at elevated risk, assessed 5 months later with a questionnaire.

RESULTS

Analyses were based on 173 patients. Compared with control patients, intervention patients were more likely to remember the campaign (81.4% vs 50.0%, P = .0001) and to correctly identify their elevated risk of melanoma (71.1% vs 42.1%, P = .001). Furthermore, intervention patients had higher levels of prevention behaviors: they were less likely to sunbathe in the summer (24.7% vs 40.8%, P = .048) and more likely to have performed skin self-examinations in the past year (52.6% vs 36.8%, P = .029). The intervention was not associated with any clear adverse effects, although there were trends whereby intervention patients were more likely to worry about melanoma and to consult their general practitioner again about the disease.

CONCLUSIONS

The combination of use of the SAMScore and general practitioner examination and counseling during consultations is an efficient way to promote patient behaviors that may reduce melanoma risk. Extending the duration of follow-up and demonstrating an impact on morbidity and mortality remain major issues for further research.