Photosensitisation and green egg yolks in laying hens caused by the feeding of ensiled alfalfa leaves.

1. The present study was carried out to determine the effects of feeding ensiled alfalfa leaves (ALS) as an alternative protein source to laying hens under the terms of an organic diet. Due to the occurrence of unexpected negative health effects and undesirable egg yolk pigmentation in the test groups the trial was prematurely stopped and further analysis was conducted to evaluate the responsible substances.2. Body weights of the test groups decreased significantly already in week 2 of the trial. Performance variables dropped. Olive green pigmented egg yolks were found in groups fed diets containing ALS. Severe comb necrosis occurred in the experimental group receiving the highest level of ALS (20%) combined with the option of free-range access and therefore natural light exposure.3. The noxious agent found in ALS, blood serum and egg yolk was the photosensitising chlorophyll derivate pheophorbid a (PPBa), deriving from a strong depletion of chlorophyll contained in the alfalfa leaves. PPBa caused the olive-green pigmentation found in yolks and led to photosensitivity in groups with the highest level of ALS in the diet in combination with light exposure.4. By aiming for high protein and amino acid levels, harvesting and processing have, unintentionally and initially unnoticed, led to a strong accumulation of phototoxic PPBa. From these results it is strongly advised not to include ensiled alfalfa leaves as a protein source in organic laying hen diets.

Selecting first-line bevacizumab-containing therapy for advanced breast cancer: TURANDOT risk factor analyses.

BACKGROUND: The randomised phase III TURANDOT trial compared first-line bevacizumab-paclitaxel (BEV-PAC) vs bevacizumab-capecitabine (BEV-CAP) in HER2-negative locally recurrent/metastatic breast cancer (LR/mBC). The interim analysis revealed no difference in overall survival (OS; primary end point) between treatment arms; however, progression-free survival (PFS) and objective response rate were significantly superior with BEV-PAC. We sought to identify patient populations that may be most appropriately treated with one or other regimen. METHODS: Patients with HER2-negative LR/mBC who had received no prior chemotherapy for advanced disease were randomised to either BEV-PAC (bevacizumab 10 mg kg(-1) days 1 and 15 plus paclitaxel 90 mg m(-2) days 1, 8 and 15 q4w) or BEV-CAP (bevacizumab 15 mg kg(-1) day 1 plus capecitabine 1000 mg m(-2) bid days 1-14 q3w). The study population was categorised into three cohorts: triple-negative breast cancer (TNBC), high-risk hormone receptor-positive (HR+) and low-risk HR+. High- and low-risk HR+ were defined, respectively, as having ⩾2 vs ⩽1 of the following four risk factors: disease-free interval ⩽24 months; visceral metastases; prior (neo)adjuvant anthracycline and/or taxane; and metastases in ⩾3 organs. RESULTS: The treatment effect on OS differed between cohorts. Non-significant OS trends favoured BEV-PAC in the TNBC cohort and BEV-CAP in the low-risk HR+ cohort. In all three cohorts, there was a non-significant PFS trend favouring BEV-PAC. Grade ⩾3 adverse events were consistently less common with BEV-CAP. CONCLUSIONS: A simple risk factor index may help in selecting bevacizumab-containing regimens, balancing outcome, safety profile and patient preference. Final OS results are expected in 2015 (ClinicalTrials.gov NCT00600340).

FOLFOX4 plus cetuximab administered weekly or every second week in the first-line treatment of patients with KRAS wild-type metastatic colorectal cancer: a randomized phase II CECOG study.

BACKGROUND: This randomized phase II study investigated first-line chemotherapy plus cetuximab administered every second week in KRAS wild-type metastatic colorectal cancer. PATIENTS AND METHODS: Patients received FOLFOX4 plus either standard weekly cetuximab (arm 1) or cetuximab (500 mg/m(2)) every second week (arm 2), until disease progression or unacceptable toxicity. Primary end point was the objective response rate (ORR). Progression-free survival (PFS), overall survival (OS), disease control rate (DCR) and safety were also investigated. The study was not powered to establish non-inferiority, but aimed at the estimation of treatment differences. RESULTS: Of 152 randomized eligible patients, 75 were treated in arm 1 and 77 in arm 2; ORRs [53% versus 62%, odds ratio 1.40, 95% confidence interval (CI) 0.74-2.66], PFS [median 9.5 versus 9.2 months, hazard ratio (HR) 0.92, 95% CI 0.63-1.34], OS (median 25.8 versus 23.0 months, HR 0.86, 95% CI 0.56-1.30) and DCR (87%) were comparable. HRs adjusted for baseline factors were 1.01 and 0.99 for PFS and OS, respectively. Frequencies of grade 3/4 adverse events in arms 1 versus 2 were similar: most common were neutropenia (28% versus 34%) and rash (15% versus 17%). CONCLUSIONS: Activity and safety of FOLFOX4 plus either cetuximab administered weekly or every second week were similar.

Computational approaches to understanding interaction and development.

Audio-visual recording and location tracking produce enormous quantities of digital data with which researchers can document children's everyday interactions in naturalistic settings and assessment contexts. Machine learning and other computational approaches can produce replicable, automated measurements of these big behavioral data. The economies of scale afforded by repeated automated measurements offer a potent approach to investigating linkages between real-time behavior and developmental change. In our work, automated measurement of audio from child-worn recorders-which quantify the frequency of child and adult speech and index its phonemic complexity-are paired with ultrawide radio tracking of children's location and interpersonal orientation. Applications of objective measurement indicate the influence of adult behavior in both expert ratings of attachment behavior and ratings of autism severity, suggesting the role of dyadic factors in these "child" assessments. In the preschool classroom, location/orientation measures provide data-driven measures of children's social contact, fertile ground for vocal interactions. Both the velocity of children's movement toward one another and their social contact with one another evidence homophily: children with autism spectrum disorder, other developmental disabilities, and typically developing children were more likely to interact with children in the same group even in inclusive preschool classrooms designed to promote interchange between all children. In the vocal domain, the frequency of peer speech and the phonemic complexity of teacher speech predict the frequency and phonemic complexity of children's own speech over multiple timescales. Moreover, children's own speech predicts their assessed language abilities across disability groups, suggesting how everyday interactions facilitate development.

Peginterferon alpha-2a (40 kDa) and ribavirin: comparable rates of sustained virological response in sub-sets of older and younger HCV genotype 1 patients.

The average age of patients initiating therapy for HCV is increasing, with older patients exhibiting lower responses to therapy than younger patients. Identification of those older patients likely to respond needs to be addressed. Using data from 569 genotype-1 patients enrolled in two phase III studies (NV15801/NV15942) randomized to peginterferon alpha-2a (40 KDa) 180 microg/week plus ribavirin 1000/1200 mg/day for 48-weeks, we investigated factors associated with sustained virological response (SVR; undetectable HCV-RNA 24-weeks post-treatment) in patients >50 years. SVR rates among patients 50 years (52%vs 39%; P = 0.0073). Older patients with a rapid virological response (RVR; undetectable HCV-RNA at treatment week 4) or complete early virological response (cEVR; detectable HCV-RNA at week 4 but HCV-RNA <50 IU/mL at week-12) demonstrated high SVR rates (83% and 61% respectively). Older patients had lower cumulative peginterferon alpha-2a exposure and significantly lower cumulative ribavirin exposure (252 g vs 304 g in younger patients; P < 0.0001). Higher relapse rates were observed in older patients (41%vs 25%; P = 0.0042). Cumulative drug exposure and achievement of RVR or cEVR were significantly predictive of SVR by multiple logistic regression analysis in patients >50 years. Other baseline characteristics predictive of SVR in those >50 years of age were lower baseline HCV-RNA level (P = 0.0067), higher ALT-ratio (P = 0.0113) and absence of cirrhosis (P = 0.0482). Response rates were high among patients >50 years without cirrhosis who maintained adequate drug exposure and those achieving an RVR or cEVR. More frequent dose modifications of ribavirin in those >50 years likely contributed to the observed higher relapse rates.

Predictive impact of rare genomic copy number variations in siblings of individuals with autism spectrum disorders.

Identification of genetic biomarkers associated with autism spectrum disorders (ASDs) could improve recurrence prediction for families with a child with ASD. Here, we describe clinical microarray findings for 253 longitudinally phenotyped ASD families from the Baby Siblings Research Consortium (BSRC), encompassing 288 infant siblings. By age 3, 103 siblings (35.8%) were diagnosed with ASD and 54 (18.8%) were developing atypically. Thirteen siblings have copy number variants (CNVs) involving ASD-relevant genes: 6 with ASD, 5 atypically developing, and 2 typically developing. Within these families, an ASD-related CNV in a sibling has a positive predictive value (PPV) for ASD or atypical development of 0.83; the Simons Simplex Collection of ASD families shows similar PPVs. Polygenic risk analyses suggest that common genetic variants may also contribute to ASD. CNV findings would have been pre-symptomatically predictive of ASD or atypical development in 11 (7%) of the 157 BSRC siblings who were eventually diagnosed clinically.

A baseline tool for predicting response to peginterferon alfa-2a in HBeAg-positive patients with chronic hepatitis B.

BACKGROUND: Peginterferon induces off-treatment responses in approximately one-third of patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B. AIM: To develop an easy-to-use baseline prediction score to identify hepatitis B virus (HBV) genotype B-/C-infected HBeAg-positive Asian patients likely to respond to peginterferon alfa-2a. METHODS: Generalised additive models, multiple logistic regression (MLR) analysis and internal validation methods were applied to data from 647 HBeAg-positive patients from China, Hong Kong and Taiwan to develop a scoring system to predict response 24 weeks after completing a 48-week course of peginterferon alfa-2a. RESULTS: Five baseline factors (age, sex, alanine aminotransferase ratio, hepatitis B surface antigen (HBsAg) level and HBV DNA level) were retained in the final MLR for HBeAg seroconversion and used to develop a scoring system from 0 to 7. Among patients with scores of 0-1, 2-3, 4 or ≥5, HBeAg seroconversion was achieved in 6.4% (6/94), 23.0% (61/265), 36.4% (67/184) and 54.8% (57/104), respectively, and a combined response (HBeAg seroconversion plus HBV DNA <2000 IU/mL) in 5.3% (5/94), 12.8% (34/265), 25.0% (46/184) and 36.5% (38/104), respectively. Among patients with scores of 0-1, 2-3, 4 or ≥5, 57.0% (53/93), 12.3% (31/253), 3.4% (6/178) and 1.0% (1/100) had HBsAg ≥20 000 IU/mL at treatment Week 12; only 3/91 (3.3%) with HBsAg ≥20 000 IU/mL experienced a combined response at 24 weeks post-treatment (negative predictive value = 97% [88/91]). CONCLUSION: A pre-treatment scoring system using readily available baseline characteristics identifies HBeAg-positive Asian patients likely to experience sustained HBeAg seroconversion after treatment with peginterferon alfa-2a.

Responses are durable for up to 5 years after completion of peginterferon alfa-2a treatment in hepatitis B e antigen-positive patients.

BACKGROUND: In the large randomised NEPTUNE study, peginterferon alfa-2a 180 µg/wk for 48 weeks produced higher hepatitis B e antigen (HBeAg) seroconversion rates 24 weeks post-treatment (36%) than a lower dose (90 µg/wk) and/or shorter duration (24 weeks) (range 14%-26%). AIM: To determine seroconversion rates 5 years after completion of treatment in NEPTUNE. METHODS: HBeAg-positive patients who completed 24 weeks' follow-up in NEPTUNE (with peginterferon alfa-2a 90 µg/wk × 24 weeks [group 1]; 180 µg/wk × 24 weeks [2]; 90 µg/wk × 48 weeks [3] or 180 µg/wk × 48 weeks [4]) were followed up. RESULTS: Three hundred and eighty three of the 544 patients in the original study were enrolled in the long-term follow-up study. Many patients (196 overall; more in groups 1-3 than 4) received nucleos(t)ide analogues or immunomodulators during follow-up, and more patients had missing data at year 5 in groups 2 and 4 (48 weeks, 50/112) than in groups 1 and 3 (24 weeks, 23/103), which confounds the planned per-protocol analysis. HBeAg seroconversion rates in groups 1, 2, 3 and 4 at year 5 were 47.5%, 50.7%, 52.2% and 67.1%, respectively, (odds ratio for group 4 versus 1-3: 2.02; 95% CI 1.21, 3.38), using multiple imputation methods for missing measurements. CONCLUSION: Seroconversion rates are durable for up to 5 years after completion of peginterferon alfa-2a therapy and, consistent with NEPTUNE, the results suggest that the licensed regimen (180 µg × 48 weeks) is more efficacious for HBeAg-positive patients than a lower dose and/or shorter treatment duration.

Randomized, double-blind, placebo-controlled trial of recombinant human erythropoietin, epoetin Beta, in hematologic malignancies.

PURPOSE: To investigate the effect of recombinant human erythropoietin (epoetin beta) on anemia, transfusion need, and quality of life (QOL) in severely anemic patients with low-grade non-Hodgkin's lymphoma (NHL), chronic lymphocytic leukemia (CLL), or multiple myeloma (MM). PATIENTS AND METHODS: Transfusion-dependent patients with NHL (n = 106), CLL (n = 126), or MM (n = 117) and a low serum erythropoietin concentration were randomized to receive epoetin beta 150 IU/kg or placebo subcutaneously three times a week for 16 weeks. Primary efficacy criteria were transfusion-free and transfusion- and severe anemia-free survival (hemoglobin [Hb] > 8.5 g/dL) between weeks 5 to 16. Response was defined as an increase in Hb > or = 2 g/dL with elimination of transfusion need. QOL was assessed by the Functional Assessment of Cancer Therapy scale. RESULTS: Transfusion-free (P =.0012) survival and transfusion- and severe anemia-free survival (P =.0001) were significantly greater in the epoetin beta group versus placebo (Wald chi(2) test), giving a relative risk reduction of 43% and 51%, respectively. The response rate was 67% and 27% in the epoetin beta versus the placebo group, respectively (P <.0001). After 12 and 16 weeks of treatment, QOL significantly improved in the epoetin beta group compared with placebo (P <.05); this improvement correlated with an increase in Hb concentration (> or = 2 g/dL). A target Hb that could be generally recommended could not be identified. CONCLUSION: Many severely anemic and transfusion-dependent patients with advanced MM, NHL, and CLL and a low performance status benefited from epoetin therapy, with elimination of severe anemia and transfusion need, and improvement in QOL.

Cocaine exposure is associated with subtle compromises of infants' and mothers' social-emotional behavior and dyadic features of their interaction in the face-to-face still-face paradigm.

Prenatal cocaine and opiate exposure are thought to subtly compromise social and emotional development. The authors observed a large sample of 236 cocaine-exposed and 459 nonexposed infants (49 were opiate exposed and 646 nonexposed) with their mothers in the face-to-face still-face paradigm. Infant and maternal behaviors were microanalytically coded. No opiate-exposure effects were detected. However, mothers of cocaine-exposed infants showed more negative engagement than other mothers. The cocaine-exposed dyads also showed higher overall levels of mismatched engagement states than other dyads, including more negative engagement when the infants were in states of neutral engagement. Infants exposed to heavier levels of cocaine showed more passive-withdrawn negative engagement and engaged in more negative affective matching with their mothers than other infants. Although effect sizes were small, cocaine exposure, especially heavy cocaine exposure, was associated with subtly negative interchanges, which may have a cumulative impact on infants' later development and their relationships with their mothers.

Spontaneous silent myocardial ischemia assessed by technetium-99m-sestamibi imaging.

We report on an 80-yr-old patient with a history of inferior myocardial infarction. The patient was injected with 15 mCi of 99mTc-sestamibi when an electrocardiogram revealed new asymptomatic inferolateral ST-segment depressions. A second 99mTc study was performed 72 hr after the initial injection and after ST-segment changes had resolved. Scintigraphic acquisitions using SPECT revealed a large reduction in photon activity in the inferolateral and inferoposterior walls with 70%-80% normalization. Therefore, 99mTc-sestamibi imaging is useful in assessing asymptomatic silent myocardial ischemia.

Comparison of dobutamine and exercise using technetium-99m sestamibi imaging for the evaluation of coronary artery disease.

Studies using dobutamine thallium-201 myocardial perfusion imaging have suggested a high sensitivity and specificity for the detection of coronary artery disease. However, few data are available comparing dobutamine with exercise stress for the detection and localization of perfusion defects. This study compared the effects of dobutamine and exercise stress using technetium-99m sestamibi single-photon emission computed tomographic imaging in the same patients in a prospective crossover trial. Twenty-four patients with a high likelihood of coronary artery disease underwent tomographic myocardial imaging at rest, after symptom-limited treadmill exercise, and after intravenous dobutamine (maximum 30 micrograms/kg/min). Tomograms of the left ventricle were divided into 20 segments and were interpreted without knowledge of patient identity or stress protocol. Dobutamine was well tolerated by all patients. Segment-by-segment concordance between exercise and dobutamine images was highly significant (kappa = 0.56, p < 0.0001). Global first-order agreement (normal vs abnormal) between exercise and dobutamine studies was 96% (kappa = 0.65, p = 0.02); global second-order agreement (normal vs fixed vs ischemic defect) was 88% (kappa = 0.45, p = 0.02). Regional first- and second-order agreement were 96 and 93%, respectively (p < 0.001 for both). Twenty patients underwent coronary angiography. Comparisons between exercise and angiography and between dobutamine and angiography were similar for both global agreement (95 vs 100%, p = NS) and regional agreement (77 vs 72%, p = NS).(ABSTRACT TRUNCATED AT 250 WORDS)

Factors related to transfusion in very low birthweight infants treated with erythropoietin.

The need for red cell transfusions is reduced but not eliminated by recombinant human erythropoietin (rhEPO) in very low birthweight (VLBW) infants. To detect factors associated with the decision to transfuse VLBW infants during rhEPO treatment and to explain rhEPO 'non-responders', the subgroup of those 120 VLBW infants who were treated with rhEPO 750 IU/kg per week in the second European Multicentre rhEPO Trial was evaluated. Sixty (50%) infants received at least one transfusion during erythropoietin treatment. Transfusion was frequent in infants with extremely low birthweight (79% for 750-999 g), low gestational age (70% for < or = 28 weeks), low initial haematocrit or low initial reticulocyte count (61% for haematocrit < or = 0.48 and reticulocytes < or = 9%, respectively). Considerable differences among centres were found for sampling blood loss, iron supply, and transfusion rate, which ranged from 13% to 73% and was related to the volume of diagnostic blood loss (19% vs 80% for blood loss < 1 vs > or = 1 ml/kg per day). The prognostic variables birthweight, initial haematocrit, and gestational age were found to be most predictive for transfusion. To improve rhEPO response in VLBW infants, there is a need to minimise diagnostic blood loss, to prevent iron deficiency, and to develop rational criteria for transfusion in preterm infants.

Prenatal drug exposure and maternal and infant feeding behaviour.

OBJECTIVE: To evaluate feeding difficulties and maternal behaviour during a feeding session with 1 month old infants prenatally exposed to cocaine and/or opiates. METHODS: The study is part of the maternal lifestyle study, which recruited 11 811 subjects at four urban hospitals, then followed 1388 from 1 to 36 months of age. Exposure to cocaine and opiates was determined by maternal interview and meconium assay. At the 1 month clinic visit, biological mothers were videotaped while bottle feeding their infants. This sample included 364 exposed to cocaine, 45 exposed to opiates, 31 exposed to both drugs, and 588 matched comparison infants. Mothers were mostly black, high school educated, and on public assistance. Videotapes were coded without knowledge of exposure status for frequency, duration and quality of infant sucking, arousal, feeding problems, and maternal feeding activity and interaction. RESULTS: No cocaine effects were found on infant feeding measures, but cocaine-using mothers were less flexible (6.29 v 6.50), less engaged (5.77 v 6.22), and had shorter feeding sessions (638 v 683 seconds). Opiate exposed infants showed prolonged sucking bursts (29 v 20 seconds), fewer pauses (1.6 v 2.2 per minute), more feeding problems (0.55 v 0.38), and increased arousal (2.59 v 2.39). Their mothers showed increased activity (30 v 22), independent of their infants' feeding problems. CONCLUSIONS: Previous concerns about feeding behaviour in cocaine exposed infants may reflect the quality of the feeding interaction rather than infant feeding problems related to prenatal exposure. However, opiate exposed infants and their mothers both contributed to increased arousal and heightened feeding behaviour.

The use of epoetin beta in anemic predialysis patients with chronic renal failure.

UNLABELLED: Two clinical studies were conducted to investigate the efficacy and safety of epoetin beta in 266 [corrected] anemic predialysis patients. Epoetin beta was administered subcutaneously either daily or thrice weekly. Mean duration of treatment was 211 days (interquartile range: 105 to 350 days). RESULTS: Renal anemia could be corrected and the regular transfusion need could be eliminated in all patients. There was no difference in the dose requirement per week between daily and thrice weekly administration of epoetin beta. Regarding the entire study population, there was no acceleration of the progression of renal failure during epoetin beta treatment nor were there any notable changes in laboratory values other than retention values. Epoetin beta was safe and well tolerated; the most important adverse event was the development or aggravation of hypertension.

All smiles are positive, but some smiles are more positive than others.

Disagreement as to whether all smiling or specific types of smiling index positive emotion early in life was addressed by examining when infants produced different types of smiling and other facial expressions. Thirteen infants were observed weekly from 1 to 6 months of age. Smiling alone--without cheek raising or mouth opening--was relatively more likely than periods without smiling both when mothers were smiling and when infants were gazing at their mothers' faces. Cheek-raise (Duchenne) smiling was relatively more likely than smiling alone only when mothers were smiling. Open-mouth (play) smiling was relatively more likely than smiling alone only when infants were gazing directly at mothers' faces. Smiling involving both cheek raising and mouth opening was relatively likely both when mothers were smiling and when infants were gazing at mothers' faces and became increasingly likely with age when both conditions co-occurred. The cheek-raise and open-mouth dimensions of smiling appear to be associated with, respectively, the amplification of processes of sharing positive affect and of visual engagement that are present to a lesser degree in smiling alone.

What's in a smile?

In positive social contexts, both adults and older infants show more Duchenne smiling (which involves high cheek raising) than non-Duchenne smiling (which does not). This study compared Duchenne and non-Duchenne smiles in early infancy for clues to their emotional significance. Infants (N = 13) from 1 to 6 months of age were videotaped weekly for 5 min in 208 face-to-face interactions with their mothers. Levels of Duchenne and non-Duchenne smiling were correlated within interactive sessions, and the 2 smiles had similar developmental trajectories. Duchenne smiles were typically preceded by non-Duchenne smiles. The results suggest these frequently contrasted types of smiles occur in similar situations and are often different temporal phases of a continuous emotional process. In contrast to adults, infant Duchenne smiles had longer durations than non-Duchenne smiles, suggesting infant smiling does not fit adult models of emotional functioning.

An event-based analysis of the coordination of early infant vocalizations and facial actions.

This study used an event-based approach to provide empirical evidence regarding the nature of coordination in 3- and 6-month-old infants. Vocalizations and facial actions of 12 normally developing infants interacting with their caregivers were coded. Coded vocalizations and facial actions were considered coordinated when they temporally overlapped. Results indicate that infants coordinated their vocalizations and facial actions more than expected by chance. Coordinated events were governed by 2 sequence patterns. When 2 communicative events were temporally associated across modalities, 1 event tended to be completely embedded within the other, and vocalizations tended to end before facial actions. This study provides new information about how infant communication is structured, confirms results from other coordination studies, and describes a new method for analysis of event-based data.

The Bayley Scales of Infant Development. II: Where to start?

This study examines whether the Bayley Scales of Infant Development-Second Edition (Bayley II) Mental Scale scores vary on the basis of which item set is considered the starting point of an infant's assessment. The Bayley II was administered to 78 12-month-old infants by certified examiners beginning with the 12-month age item set. A second certified examiner then administered 10 additional items that completed the 11-month and 13-month age item sets. Of the 78 infants tested, 73 (94%) met basal and ceiling criteria in all three item sets. Three separate Mental Developmental Index (MDI) scores were calculated using 12-month norms for each subject, which were based on the raw scores generated from the 11-, 12-, and 13-month age item sets. Scores calculated on the 11-month set were significantly lower than those on the 12-month set, which were in turn significantly lower than those on the 13-month set. When tested on the 11-month instead of on the 12-month item set, twice as many infants received lower than normal (< 85) MDI scores, indicating an impact on referability decisions. Minor adjustments in administration of the Bayley II, such as those based on assumptions regarding an infant's current level of functioning, significantly affect infant test scores and eligibility for follow-up services. Standardized use of this test should minimize variability in test scores.

Human monkeypox in Kasai Oriental, Zaire (1996-1997).

Monkeypox is an orthopoxvirus with enzootic circulation in the rainforests of central and western Africa; the virus can be transmitted to humans and cause a syndrome clinically similar to smallpox (e.g., pustular rash, fever, respiratory symptoms, and in