Shelley Hurwitz

Prolonged Granulocytopenia: The Major Risk Factor for Invasive Pulmonary Aspergillosis in Patients with Acute Leukemia

A case-control study of patients with acute leukemia was done to identify significant risk factors for invasive pulmonary aspergillosis by reviewing the medical histories of 15 cases of pathologically proven invasive pulmonary aspergillosis and 45 controls. A history of lung or sinus disease, smoking, and multiple recurrences of leukemia did not increase the risk of invasive pulmonary aspergillosis. Cases and controls received similar chemotherapeutic regimens, and exposure to aminoglycosides, carbenicillin, trimethoprim-sulfamethoxazole, or corticosteroids was not significantly associated with development of invasive pulmonary aspergillosis. Among the factors tested, only granulocytopenia was associated with development of invasive pulmonary aspergillosis. Early in the course of granulocytopenia, patients developed signs of invasive pulmonary aspergillosis at a rate of approximately 1% per day. As the duration of granulocytopenia increased, the rate increased, approximating 4.3% per day between the 24th and 36th days. Of the 13 patients remaining granulocytopenic at 28 days, 7 had developed signs of invasive pulmonary aspergillosis. For patients with acute leukemia, granulocytopenia persisting longer than three weeks is the major risk factor for developing invasive pulmonary aspergillosis.

Identification of Serum Soluble ST2 Receptor as a Novel Heart Failure Biomarker

Background—Using genomic technology, we previously identified an interleukin-1 receptor family member, ST2, as a gene markedly induced by mechanical strain in cardiac myocytes. The soluble receptor form of ST2 is secreted and detectable in human serum. This study tested the hypothesis that soluble ST2 levels in the serum of patients with severe chronic heart failure are increased in patients with neurohormonal activation. Methods and Results—Serum samples, clinical variables, and neurohormone levels from the PRAISE-2 heart failure trial (NYHA functional class III-IV; end point, mortality or transplantation) were analyzed. ST2 serum measurements were performed with ELISA on samples from 161 patients obtained at trial enrollment and from 139 of the same patients obtained 2 weeks after trial enrollment. Baseline ST2 levels were correlated with baseline B-type natriuretic peptide (BNP) levels (r =0.36, P <0.0001), baseline proatrial natriuretic peptide (ProANP) levels (r =0.36, P <0.0001), and baseline norepinephrine levels (r =0.39, P <0.0001). The change in ST2 was significant as a univariate predictor of subsequent mortality or transplantation (P =0.048), as was baseline BNP (P <0.0001) and baseline ProANP (P <0.0001). In multivariate models including BNP and ProANP, the change in ST2 remained significant as a predictor of mortality or transplantation independent of BNP and ProANP. Conclusions—Serum soluble ST2 is a novel biomarker for neurohormonal activation in patients with heart failure. In patients with severe chronic NYHA class III to IV heart failure, the change in ST2 levels is an independent predictor of subsequent mortality or transplantation.

Upward direction, mental rotation, and discrimination of left and right turns in maps.

Abstract Whereas, the only direction of which we have always had immediate knowledge is the gravitationally defined vertical, the directions that have beeen most important for finding our way about are largely orthogonal directions along the generally horizontal ground. The first half of the paper argues that the concept of an upward direction has consequently been extended to represent horizontal directions that are (1) uphill, however slightly, (2) upward in the metaphorical sense of toward a salient or important reference object or location, (3) northward in the global environmental frame, or (4) straight ahead in the viewers egocentric frame. The second half empirically explores this last coupling, between upwards and straight ahead, by two chronometric experiments on the interpretation of bends in a line, as right or left turns on a map. Interpretation time increased markedly with angular departure from upright of the line going into the turn, suggesting that such interpretation requires a mental rotation.

Risk factors for nosocomial candidemia: A case-control study in adults without leukemia*

PURPOSE The purpose of this study was to define risk factors for nosocomial candidemia in adult patients without leukemia at a tertiary care medical center. PATIENTS AND METHODS All patients with nosocomial candidemia between August 1, 1981, and October 31, 1984, were included if they met strict selection criteria and did not have acute or chronic leukemia. For each case, one control was selected from among patients admitted during the same month/year and matched for hospital service and duration of hospitalization up to the first blood culture that grew Candida species. Logistic regression was used to obtain estimates of risk after simultaneously controlling for other variables. RESULTS Candida albicans caused 24 of the 48 fungemias studied. The risk factors identified included the presence of a central line (odds ratio, 26.4; 95% confidence interval, 1.5 to 451.1); bladder catheter (13.0 1.3 to 131.4); two or more antibiotics (25.1, 2.1 to 318); azotemia (22.1, 2.2 to 223.2); transfer from another hospital (21.3, 1.7 to 274.5); diarrhea (10.2, 1.03 to 101.4); and candiduria (27.0, 1.7 to 423.5). A prior surgical procedure was associated with lowered risk (0.1, 0.01 to 0.9), suggesting perhaps that medical service patients are at higher risk than those on surgical services. Because total parenteral nutrition was always administered by means of a central line, it could not be shown to increase the risk over that conferred by a central line alone. CONCLUSIONS This study has defined seven major risk factors for nosocomial candidemia. These findings should facilitate development of rational approaches to preventing infection and may assist clinicians in identifying those patients in whom this life-threatening complication is likely to occur.

Natural History of Benign Solid and Cystic Thyroid Nodules

Context Although benign thyroid nodules are common, we know relatively little about their natural history. Contribution This observational study from a single tertiary care facility used repeated ultrasonography to show that benign thyroid nodules typically increase in volume over a 3- to 5-year period. Solid nodules grew more than cystic nodules, and only 1 of 74 reaspirated nodules was malignant. Implications Nodule growth alone does not predict malignancy. The Editors Thyroid nodules are present in nearly 50% of adults, increasing in prevalence with age (1). The evaluation of thyroid nodules that measure 1 cm or greater in diameter typically includes a screening measure of serum thyroid-stimulating hormone (TSH) levels and fine-needle aspiration (FNA). Most FNA results are benign (90% to 95%), and follow-up examinations are advised. Recommendations include periodic clinical examinations or ultrasonography, with or without suppressive l-thyroxine therapy (1, 2). Nodules that increase in size during follow-up are often regarded as suspicious for malignancy, and repeated FNA or surgery is advised (3-6). Data supporting these recommendations are limited, however, as few reports have evaluated thyroid nodule growth using the most sensitive technique, high-resolution ultrasonography. Furthermore, criteria defining nodule growth are inconsistent; some guidelines use an increase in maximal diameter of greater than 50%, while others suggest an increase in maximal diameter greater than 5 mm or an increase in calculated volume greater than 15% (5-10). We used ultrasonography of thyroid nodules to determine the natural history of cytologically benign thyroid nodules over a 1-month to 5-year follow-up period. Methods We retrospectively reviewed the records of all patients referred to the dual-discipline Thyroid Nodule Clinic at Brigham and Womens Hospital, Boston, Massachusetts, for evaluation of nodular thyroid disease between 1995 and 2000. All patients referred to the clinic underwent ultrasonography of the thyroid by a radiologist and ultrasonography-guided FNA of nodules measuring 1 cm or greater in maximal diameter by an endocrinologist. All ultrasonography evaluations were adequate for review and interpretation. All patients with benign cytology on initial FNA were advised to schedule follow-up ultrasonography 9 to 12 months later. Repeated FNA was performed on the follow-up visit at the discretion of the endocrinologist, usually because of nodule growth. The study sample included all patients with nodules with benign cytologic results on the initial visit who returned for follow-up ultrasonography within the 5-year period. Thyroid ultrasonography was performed by one of three radiologists using a 5- to 15-MHz transducer. The length, width, and depth of each nodule were reported, and each nodule was classified as solid, less than 25% cystic, 25% to 50% cystic, 50% to 75% cystic, or greater than 75% cystic. Nodule volume was calculated by using the formula for a rotational ellipsoid (length width depth /6) (7, 11, 12). Ultrasonography-guided FNA was performed with a 25-gauge needle (three to four aspirations per nodule), and specimens were processed by using the Thin-Prep technique (Cytyc Corp., Boxborough, Massachusetts). All slides were read by a cytopathologist at Brigham and Womens Hospital. Specimens were considered benign when six or more groups of benign follicular cells (each group containing 15 cells) were identified without atypical features. Repeated ultrasonographies were performed, and findings were directly compared with the previous images. Change in nodule size over the interval between examinations was assessed by using three criteria: 1) change in maximal diameter greater than 50% [7, 8, 12, 13]; 2) change in maximal diameter of 3 mm or more; 3) change in calculated volume of 15% or more (11, 14). The latter two criteria are defined by established inaccuracy rates for each method (11, 15). The Investigational Review Board of Brigham and Womens Hospital granted permission to perform this review. Descriptive statistics are presented according to nodule or patient as appropriate. The main outcome for the single-variable and multivariable predictive models was nodule growth, defined as an increase in volume of 15% or greater. Single-variable and multivariable mixed-effects logistic regression was used to predict growth, while accounting for the correlation structure in the data where some patients had more than one nodule (16). Potential predictors were the time between examinations, cystic content (solid, <25% cystic, 25% to 50% cystic, 50% to 75% cystic, or >75% cystic), TSH level (mIU/L), l-thyroxine use, age, and sex. Unadjusted and adjusted odds ratios and 95% CIs were calculated. Time to growth was determined by using life-table methods. Data were analyzed by using SAS software, version 8.2 (SAS Institute, Inc., Cary, North Carolina). The funding sources had no role in the design, conduct, or reporting of the study or the decision to publish the manuscript. Results A total of 1009 patients were examined in the Thyroid Nodule Clinic between 1995 and 2000, and 1358 nodules were biopsied. On initial FNA, 854 nodules (in 700 patients) measured 1 cm or greater in maximal diameter with benign cytologic results. Two hundred sixty-eight patients (38%) with 330 benign thyroid nodules (39%) returned for follow-up ultrasonography, with a mean interval of 20 months (range, 1 to 65 months) between examinations (Appendix Figure). The baseline demographic and ultrasonography characteristics of these 268 patients and their nodules were similar to those of the 432 patients who did not return for follow-up (Table 1). Table 1. Demographic and Ultrasonography Characteristics of Patients with a Benign Thyroid Nodule 1 cm in Maximal Diameter Who Returned for Follow-up Ultrasonography as Recommended Compared with Those Who Did Not Change in nodule size over each patients follow-up period was assessed by three methods to facilitate comparison with previous studies. With use of a greater than 50% change in maximal diameter, 14 nodules (4%) were determined to have increased in size upon repeated ultrasonography. With evaluating change in maximal diameter of 3 mm or greater or change in calculated volume (cm3) of 15% or greater, 86 nodules (26%) and 129 nodules (39%), respectively, were determined to have increased in size on follow-up ultrasonography. The time interval between examinations was significantly correlated with nodule growth (r = 0.22; P < 0.001). Table 2 shows mixed-models logistic regression analysis for prediction of thyroid nodule growth (volume change 15%). Time between examinations and lower cystic content remained statistically significant predictors of growth in the final multivariable model. Each year, the background odds of growth increased by 50%. The estimated median time to achieve volume growth of 15% or greater was 35 months (95% CI, 29 to 41 months). The estimated proportion with growth was 53% (CI, 46% to 61%) at 3 years and 89% (CI, 81% to 97%) at 5 years using life-table methods. The patients age, sex, baseline serum TSH concentration, or l-thyroxine use did not predict nodule growth. Table 2. Single-Variable Predictors and Final Multivariable Model To Predict Thyroid Nodule Growth (Volume Increase 15%) Sixty-one patients underwent repeated FNA at the time of the second ultrasonography. The nodules in this group were larger on initial examination (2.7 cm vs. 2.3 cm; P = 0.001) and had increased in volume by an average of 69% during follow-up compared with 14% in those nodules not rebiopsied (P < 0.001). Patient characteristics were similar except for a longer interval between examinations (28 months vs. 18 months) and younger age (43 years vs. 48 years) noted among the rebiopsied group. One of the 74 repeated FNA samples suggested a follicular neoplasm, and the remainder were benign. The nodule was removed; it was a poorly differentiated papillary carcinoma. It had enlarged from 10.1 cm3 to 18.1 cm3 in volume (an 80% increase) over 38 months. Discussion We used ultrasonography to assess the natural history of 330 benign thyroid nodules measuring 1 cm or more in maximal diameter followed for a mean period of 20 months. Although the 268 patients (with 330 nodules) represent only 39% of the benign nodules seen in the Brigham and Womens Hospital Thyroid Nodule Clinic between 1995 and 2000, they appear to be representative of the whole group with respect to demographic and nodule characteristics. Using the most rigorous criteria ( 15% increase in volume), we documented growth in 39% of benign thyroid nodules during follow-up, which indicates that many such nodules grow. Consistent with our findings, Brander and colleagues (10) found that 35% of benign nodules increased in size over 4.9 to 5.6 years. However, the criteria for growth were not defined, and minimal data on repeated FNA were provided (10). Similarly, Papini and colleagues (15) documented an increase in mean nodule volume among patients in the control group of a 5-year randomized study that assessed the efficacy of l-thyroxine suppression therapy for nodular goiter. Our results also support previous conclusions that more cystic nodules are less likely to grow compared with nodules with a greater solid component (5). Current opinion suggests that increasing nodule size has modest but significant power for predicting thyroid cancer (2). Kuma and colleagues found malignancy in 26% of previously unbiopsied nodules that increased in size over a 10- to 30-year period (5). A follow-up study 2 years later reported a malignancy rate of 4.5% among nodules that were previously found to be benign on FNA and subsequently grew (although no definition of growth was provided) (6). In our study, only 1 of 74 rebiopsied nodules was malignant on repeated FNA biopsy. Although only 22% of nodules seen in follow-up were rebiopsied, this group had s

Prognosis of status epilepticus: role of aetiology, age, and consciousness impairment at presentation.

Background: Identification of outcome-predictive factors could lower risk of under- or over-treatment in status epilepticus (SE). Older age and acute symptomatic aetiology have been shown to predict mortality, but other variables are controversial and level of consciousness has received relatively little attention. The objective of this study was to assess variables predictive of mortality, particularly those available at presentation. Methods: The discharge database (1997–2004) of two university hospitals was screened for adult patients with EEG confirmed SE, excluding cerebral anoxia. Outcome at discharge (mortality, return to baseline clinical conditions) was analysed in relation to demographics, clinical features, and aetiology. Aetiologies were also classified based on whether or not they were potentially fatal independently of SE. Results: Mortality was 15.6% among 96 patients with a first SE episode, 10 of whom also experienced recurrent SE during the study period. Eleven other patients had only recurrent SE. Mortality was 4.8% among these 21 patients with recurrent SE. Return to baseline condition was more frequent after recurrent than incident SE (p = 0.02). For the first SE episode, death was associated with potentially fatal aetiology (p = 0.01), age ⩾65 (p = 0.02), and stupor or coma at presentation (p = 0.04), but not with gender, history of epilepsy, SE type, or time to treatment ⩾1 h. Conclusions: At initial evaluation, older age and marked impairment of consciousness are predictive of death. Surviving a first SE episode could lower the mortality and morbidity of subsequent episodes, suggesting that underlying aetiology, rather than SE per se, is the major determinant of outcome.

Reduced hypothalamic-pituitary and sympathoadrenal responses to hypoglycemia in women with fibromyalgia syndrome ☆

PURPOSE To perform a detailed comparison of the hypothalamic-pituitary-adrenal axis and the sympathoadrenal system in women with and without fibromyalgia. SUBJECTS AND METHODS Fifteen premenopausal women who met the 1990 American College of Rheumatology criteria for the diagnosis of fibromyalgia and 13 healthy, premenopausal women were enrolled. We measured baseline 24-hour urinary free cortisol levels and evening and morning adrenocorticotropic hormone (ACTH) and cortisol levels, performed stepped hypoglycemic hyperinsulinemic clamp studies in which serum glucose levels were decreased from 5.0 to 2.2 mmol/L, and compared the effects of infusions of placebo and ACTH. RESULTS Women with fibromyalgia had normal 24-hour urinary free cortisol levels and normal diurnal patterns of ACTH and cortisol. There was a significant, approximately 30%, reduction in the ACTH and epinephrine responses to hypoglycemia in women with fibromyalgia compared with controls. Prolactin, norepinephrine, cortisol, and dehydroepiandrosterone responses to hypoglycemia were similar in the two study groups. In subjects with fibromyalgia, the epinephrine response to hypoglycemia correlated (P = 0.01) inversely with overall health status as measured by the fibromyalgia impact questionnaire. Graded ACTH infusion revealed similar increases in cortisol in women with fibromyalgia and healthy controls. CONCLUSIONS Patients with fibromyalgia have an impaired ability to activate the hypothalamic-pituitary portion of the hypothalamic-pituitary-adrenal axis as well as the sympathoadrenal system, leading to reduced ACTH and epinephrine responses to hypoglycemia.

Development of circulatory-renal limitations to angiotensin-converting enzyme inhibitors identifies patients with severe heart failure and early mortality ☆

OBJECTIVES This study examined the hypothesis that patients who develop angiotensin-converting enzyme inhibitor intolerance attributable to circulatory-renal limitations (CRLimit) have more severe underlying disease and worse outcome. BACKGROUND Although the renin-angiotensin system contributes to the progression of heart failure (HF), it also supports the failing circulation. Patients with the most severe disease may not tolerate inhibition of this system. METHODS Consecutive inpatient admissions to the cardiomyopathy service of the Brigham and Womens Hospital between 2000 and 2002 were reviewed retrospectively for initial profiles, discharge medications, and documented reasons for discontinuation of angiotensin-converting enzyme inhibitors. Outcomes of death and transplantation were determined. RESULTS Of the 259 patients, 86 were not on an angiotensin-converting enzyme inhibitor at discharge. Circulatory-renal limitations of symptomatic hypotension, progressive renal dysfunction, or hyperkalemia were documented in 60 patients (23%); other adverse effects, including cough, in 24 patients; and absent reasons in 2 patients. Compared with patients on angiotensin-converting enzyme inhibitors, patients with CRLimit were older (60 vs. 55 years; p = 0.006), with longer history of HF (5 vs. 2 years; p = 0.009), lower systolic blood pressure (104 vs. 110 mm Hg; p = 0.05), lower sodium (135 vs. 138 mEql/l; p = 0.002), and higher initial creatinine (2.5 vs. 1.2 mg/dl; p = 0.0001). Mortality was 57% in patients with CRLimit and 22% in the patients on angiotensin-converting enzyme inhibitors during a median 8.5-month follow-up (p = 0.0001). CONCLUSIONS Development of CRLimit to angiotensin-converting enzyme inhibitor intolerance identifies patients with severe disease who are likely to die during the next year. New treatment strategies should be targeted to this population.

Using Daily Text-Message Reminders to Improve Adherence With Oral Contraceptives: A Randomized Controlled Trial

OBJECTIVE: To estimate whether women receiving daily text-message reminders have increased oral contraceptive pill adherence compared with women not receiving reminders. METHODS: This randomized controlled trial estimated whether there was an effect of daily text-message reminders on oral contraceptive pill adherence of new oral contraceptive pill users. Pill-taking was tracked for 3 months by an electronic monitoring device with wireless data collection. During the study period, participants assigned the intervention received a daily reminder text message. Eighty-two women were assigned randomly to detect a 1.6±2.0 pill difference (90% power, 5% &agr;, 15% dropout). RESULTS: Participants were 79% white, non-Hispanic, 99% high school graduates, and 99% nulliparous with a mean age of 22 years. Most reported condom use with past coital activity, and more than half reported prior emergency contraception use. The mean number of missed pills per cycle did not differ significantly between the groups: 4.9±3.0 for the text-message group and 4.6±3.5 for the control group (P=.60). The number of missed pills per cycle increased over the course of the study, but this pattern did not increase differentially between the groups. Adherence recorded by the electronic monitoring device indicated much poorer adherence than that recorded by patient diaries. Despite poor pill-taking, there were no pregnancies. CONCLUSION: Daily text-message reminders did not improve oral contraceptive pill adherence. Although the lack of benefit may be attributed to the frequent use of alternative reminder systems in the control group, the rate of missed pills when measured objectively was still very high in both groups. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov, www.clinicaltrials.gov, NCT00733707. LEVEL OF EVIDENCE: I

A pilot study evaluating ceftriaxone and penicillin G as treatment agents for neurosyphilis in human immunodeficiency virus-infected individuals

To compare intravenous (iv) ceftriaxone and penicillin G as therapy for neurosyphilis, blood and CSF were collected before and 14-26 weeks after therapy from 30 subjects infected with human immunodeficiency virus (HIV)-1 who had (1) rapid plasma reagin (RPR) test titers >/=1&rcolon;16, (2) reactive serum treponemal tests, and (3) either reactive CSF-Venereal Disease Research Laboratory (VDRL) tests or CSF abnormalities: (a) CSF WBC values >/=20/microL or (b) CSF protein values >/=50 mg/dL. At baseline, more ceftriaxone recipients had skin symptoms and signs (6 [43%] of 14 vs. 1 [6%] of 16; P=.03), and more penicillin recipients had a history of neurosyphilis (7 [44%] of 16 vs. 1 [7%] of 14; P=.04). There was no difference in the proportion of subjects in each group whose CSF measures improved. Significantly more ceftriaxone recipients had a decline in serum RPR titers (8 [80%] of 10 vs. 2 [13%] of 15; P=. 003), even after controlling for baseline RPR titer, skin symptoms and signs, or prior neurosyphilis were controlled for. Differences in the 2 groups limit comparisons between them. However, iv ceftriaxone may be an alternative to penicillin for treatment of HIV-infected patients with neurosyphilis and concomitant early syphilis.