Lessons Learned From a Randomized Controlled Trial of Short-Course Intravenous Antibiotic Therapy for Erysipelas and Cellulitis of the Lower Limb (Switch Trial).

BACKGROUND: The diagnosis of cellulitis is made clinically without a gold standard diagnostic test, and cellulitis has many disease mimics. There is currently no consensus for optimal antimicrobial treatment duration or method of antimicrobial delivery. METHODS: This was a randomized controlled open-label multicenter trial to determine the safety and efficacy of 24 hours of intravenous (IV) therapy compared with ≥72 hours of IV therapy, both followed by oral therapy to a maximum of 7-10 days' duration for the treatment of lower limb cellulitis. RESULTS: Over 40 months, 80 patients were recruited. Thirty-nine patients were assigned to 24 hours of IV antibiotics and 41 to ≥72 hours of IV antibiotics. The mean duration (range) of IV antibiotics in the 24-hour group was 25.5 (17-40) hours, and in the ≥72-hour group it was 78 (41.5-210) hours. Three patients in the 24-hour arm and 4 patients in the ≥72-hour arm were excluded from the analysis due to withdrawal from the trial. Analysis of the remaining patients revealed that 6 patients (4 in the intervention arm and 2 in the control arm) did not achieve an adequate response to therapy. Only 1 patient experienced self-limiting adverse effects of treatment. CONCLUSIONS: The noninferiority of short-course IV therapy cannot be determined from this trial. Challenges included resource limitations for recruitment, misdiagnosis, participant withdrawal, and subjective responses to therapy based on visual assessment by treating clinicians. Further studies are needed to determine if short-course IV therapy is a suitable treatment option. AUSTRALIA COUNCIL OF CLINICAL TRIALS REGISTRY NO: ACTRN12613001366741.

Detailed analysis of chick optic fissure closure reveals Netrin-1 as an essential mediator of epithelial fusion.

Epithelial fusion underlies many vital organogenic processes during embryogenesis. Disruptions to these cause a significant number of human birth defects, including ocular coloboma. We provide robust spatial-temporal staging and unique anatomical detail of optic fissure closure (OFC) in the embryonic chick, including evidence for roles of apoptosis and epithelial remodelling. We performed complementary transcriptomic profiling and show that Netrin-1 (NTN1) is precisely expressed in the chick fissure margin during fusion but is immediately downregulated after fusion. We further provide a combination of protein localisation and phenotypic evidence in chick, humans, mice and zebrafish that Netrin-1 has an evolutionarily conserved and essential requirement for OFC, and is likely to have an important role in palate fusion. Our data suggest that NTN1 is a strong candidate locus for human coloboma and other multi-system developmental fusion defects, and show that chick OFC is a powerful model for epithelial fusion research.

White-coat hypertension and sex.

OBJECTIVES: To compare, by sex, selected behavioral and biologic characteristics among normotensive, white-coat hypertensive, and essential hypertensive patients, and to assess the similarities and differences in these characteristics between men and women diagnosed as having white-coat hypertension. METHODS: The subjects of this study were 764 men (80 normotensives, 112 white-coat hypertensives, and 572 essential hypertensives) and 442 women (53 normotensives, 81 white-coat hypertensives and 308 essential hypertensives) who were a nonrandom subset of a larger cohort of patients being assessed to determine the prognostic significance of ambulatory blood pressure measurements. Physician-measured technician-measured and ambulatory (average awake and asleep) blood pressures, daytime blood pressure variability, the difference between awake and sleeping blood pressures, cholesterol levels, plasma renin activity (PRA) and anthropometric and demographic characteristics were compared across the patient classifications within each sex group and between male and female white-coat hypertensives using one-way analysis of variance. Student's t tests and chi squared analysis. RESULTS: Among men, cholesterol levels of normotensives were significantly lower than those of either white-coat or essential hypertensives (P < 0.05 and P < 0.01, respectively). White-coat hypertensives were significantly younger than the essential hypertensives. The ambulatory and technician-measured blood pressures of the white-coat hypertensives were similar to those of the normotensives, as were most measures of variability of blood pressure. Among women, there were no differences in cholesterol level; however, white-coat hypertensives had lower PRA than did the essential hypertensives (P < 0.01) In contrast to the men, women with white-coat hypertension were similar in age to those with essential hypertension, and 10 years older than normotensives (P < 0.01). The ambulatory blood pressures of white-coat hypertensives were similar to those of normotensives, but their technician-measured blood pressures were intermediate between those of the normotensive and essential hypertensive groups. The daily variability of diastolic blood pressure among the white-coat-hypertensive women was greater than that of the normotensive women and similar to that of the essential hypertensive women. For all other measures of variability, data for white-coat-hypertensive women were similar to those for the normotensive women. There was no anthropometric or demographic difference among the patients either for men or for women. White-coat-hypertensive women were older than white-coat-hypertensive men and had higher systolic blood pressures and variabilities of blood pressure (P < 0.05). They also had lower PRA. CONCLUSIONS: These results are consistent with the ideas that the phenomenon of white-coat hypertension is similar for the two sexes, women may exhibit white-coat hypertension at a greater age than do men, and women with white-coat hypertension may further exhibit a broader white-coat effect, reflected in blood pressures measured by other medical personnel.

Anxiety coping style and daily blood pressure variation of female nurses.

OBJECTIVE: To examine how the style of coping with anxiety influences ambulatory blood pressures measured in work and home environments for 63 women aged 34 +/- 8 years employed as nurses. METHODS: Awake ambulatory blood pressures measured at work (n = 38 readings) and at home (n =7 readings) were compared among nurses who had been classified as belonging to four anxiety-coping-style groups: low anxious repressive (n = 18 work, n = 16 home), high anxious defensive (n = 4 work, n = 4 home) true low anxious (n = 21 work, n = 20 home) and true high anxious (n = 19 work, n = 18 home). The four anxiety-coping-style groups were determined by cross-classifying the women upon the basis of their scores on the Marlowe-Crowne Social Desirability Scale (cutoff at 18) and the Taylor Manifest Anxiety Scale (cutoff at 14). RESULTS: Average systolic blood pressures at work and at home among nurses with a low anxious repressive coping style were significantly lower than were those of nurses with a high anxious defensive coping style (P < 0.05) and a true low anxious coping style ( P < 0.025). Nurses with a low anxious repressive coping style also had lower diastolic blood pressures at work than did those with a high anxious defensive coping style ( P < 0.05) and lower diastolic blood pressures at home than did those with a true anxious coping style ( P < 0.01). Finally, subjects with a high anxious defensive coping style had significantly higher systolic blood pressures at work and at home (P < 0.05) and higher diastolic blood pressures at work than did nurses with a true high anxious coping style. The effects of the style of coping on the variation of work and home blood pressures were independent of several covariates including weight, perceived stress, smoking, alcohol, postural variation, and number of children. The univariate scales of Social Desirability and Anxiety also had no effect on the variability of the blood pressure. CONCLUSION: Among employed women, the extent of the reponse of the blood pressure to stresses in the work and home environments could be infoluenced by the style of coping with anxiety. Furthermore, the effects of personality constructs such as the style of coping, which are defined by the interaction of psychologic dimensions, may reflect better the complexity of behavioral influences on the blood pressure than do the univariate psychometric measures of which they are composed.

Ambulatory blood pressure variation and plasma renin activity in hypertensive women.

OBJECTIVE: To examine and compare the relationships between the level of plasma renin activity (PRA) and ambulatory blood pressure variability for hypertensive women aged under 45 years (n = 72, aged 36 +/- 6 years) and for women aged over 50 years (n = 175, aged 61 +/- 8 years). METHODS: The 247 white women studied were a nonrandom subset of a larger cohort of patients being assessed to determine the prognostic significance of ambulatory blood pressure measurements. The average awake ambulatory blood pressures (a minimum of 30 readings during at least 8 h), their SD and the coefficient of variation of the awake ambulatory blood pressures (awake SD/average awake blood pressure) of the women were examined by age group and three levels of PRA (less than 1.0, 1.0-4.0, and greater than 4.0 ng/ml per h) using two-way analysis of variance. The PRA was determined at the time of ambulatory monitoring. RESULTS: For the women aged 50 years and older, the average awake diastolic blood pressure was higher among women who had PRA greater than 4.0 ng/ml per h than it was among women who had PRA less than 1.0 ng/ml per h (P < 0.05). The average awake systolic blood pressure and systolic blood pressure variability were greater among women aged over 50 years than they were among women aged 45 years (P < 0.05). There were no significant relationships between the ambulatory blood pressure variability and the PRA, although the systolic blood pressure variability tended to be associated with the PRA among women aged under 45 years. These results contrasted sharply to previously reported findings among men, for whom there was an inverse relationship between the blood pressure and the PRA, particularly among those aged over 45 years, and a powerful positive association between measures of the awake ambulatory diastolic pressure variability and the PRA, again among older men. CONCLUSION: There seems to be a sex difference between hypertensive men and women in the relationship between the PRA and the ambulatory blood pressure variability. This difference might be related to factors associated with the menstrual cycle of women, although other biologic and behavioral influences may also play a role.

Relations of ambulatory blood pressure level and variability to left ventricular and arterial function and to left ventricular mass in normotensive and hypertensive adults.

OBJECTIVE: To assess the relationships between the level and variability of ambulatory blood pressure and left ventricular and arterial function. METHOD: We related 24 h ambulatory systolic blood pressure (SBP) and diastolic blood pressure (DBP), measures of their variability and clinic blood pressures to echocardiographic measures of left ventricle geometry and systolic function, total peripheral resistance, and the pulse pressure: stroke volume ratio as a measure of arterial stiffness in 58 normotensive and 222 unmedicated hypertensive adults. RESULTS: For hypertensive patients and for the entire population, awake and home ambulatory as well as technician-measured DBP were negatively related to left ventricle midwall fractional shortening (MWS) and to MWS as a percentage of the value predicted for end-systolic stress (afterload-corrected MWS), with inconsistent relations with SBP. Similarly, the SD and coefficient of variation of awake ambulatory DBP, but not SBP, were negatively related to both measures of left ventricle midwall function. Hypertensive patients in the lowest quintile of afterload-corrected MWS had similar physician-measured but higher ambulatory awake and home as well as technician-measured DBP, but not SBP, and higher SD of awake SBP and DBP than did those with higher afterload-corrected MWS. Ambulatory awake, home, and sleep as well as technician-measured DBP, but not SBP, were positively related to total peripheral resistance at rest whereas all components of ambulatory SBP, but not DBP, were positively related to the resting p;ulse pressure: stroke index ratio, a measure of arterial stiffness. We detected no relation between the nocturnal dip in blood pressure and any measure of left ventricular or arterial function or left ventricle geometry. Finally, left ventricle mass and relative wall thickness were related most strongly to awake and home ambulatory SBP whereas left ventricular relative wall thickness was also related to the SD of awake DBP. CONCLUSION: For this population of predominantly hypertensive unmedicated adults, ambulatory blood pressures during waking hours and at home were related to left ventricular and arterial function, the strongest relations being negative ones of DBP with left ventricular midwall function and positive ones of ambulatory DBP with peripheral resistance and ambulatory SBP with a measure of arterial stiffness. For this population the nocturnal dip of blood pressure was not related to measures either of cardiovascular function or of left ventricular structure.

Sex differences in casual and ambulatory blood pressure responses to extreme changes in dietary sodium.

OBJECTIVE: To compare the awake ambulatory and seated casual blood pressure responses to extreme changes in dietary sodium during a 4-month period between borderline hypertensive men (n = 24, aged 51+/- 7 years) and women (n = 8, aged 47+/- 8 years). METHODS: Seated casual and awake ambulatory (over an average of 9 h, n = 32 readings) blood pressures were recorded at the end of 1-month trials of low (24 +/- mmol/day for men, 32 +/- 19 mmol/day for women) and high (330 +/- 101 mmol/day for men, 298 +/- 76 for women) intakes of dietary sodium. There was a 1-month interim period between the two trial periods and energy and potassium intake were maintained constant over the entire course of the study. RESULTS: Among men, there was a similar average increase in blood pressure on going from the low- to the high-sodium diets according to the two methods of measurement, but among women there was a significant difference between the methods, such that the change in ambulatory blood pressure was less than the change in casual blood pressure. Women's casual blood pressure increased by 14/7 mmHg more than did their ambulatory blood pressure, whereas men's ambulatory blood pressure increased by 5/2 mmHg more than did their casual blood pressure (sex difference P < 0.009 for systolic and P < 0.037 for diastolic blood pressures). Finally, there was at best only modest concordance between changes in casual and ambulatory blood pressures between diets in individual patients, regardless of their sex, although men were more likely to have similar changes in their casual and ambulatory measurements than were women. CONCLUSION: The determination of the sensitivity of blood pressure to dietary sodium intake may depend upon how blood pressure is measured. There may also be an interaction between sex and blood pressure measurement technique that could affect the determination of salt-sensitivity differences between men and women.

Relation of arterial pressure level and variability to left ventricular geometry in normotensive and hypertensive adults.

OBJECTIVES: To assess the impact of blood pressure level and variability on left ventricular geometry. METHODS: Twenty-four-hour ambulatory systolic blood pressure (SBP) and diastolic blood pressure (DBP) were related to echocardiographic left ventricular geometry in 76 normotensive and 245 hypertensive adults. RESULTS: The differences in SBP and DBP between hypertensive patients with concentric hypertrophy - the most prognostically adverse left ventricular pattern - and those with other ventricular geometric patterns were greater for ambulatory awake and home blood pressure (+8 to +15/+3 to +7 and +11 to +16/+4 to +7 mmHg) than they were for physician-measured clinic bloiod pressure (+7 to +15/0 to +5 mmHg). The white-coat effect (clinic minus ambulatory awake SBP) was greatest in hypertensive patients with eccentric left ventricular hypertrophy (17 +/- 19 mmHg) and was least in those with concentric hypertrophy (9 +/- 14 mmHg); no patient with concentric hypertrophy had a normal ambulatory blood pressure. The within-patient SD of awake ambulatory blood pressure was increased in patients with concentric hypertrophny, independent of covariates, as was the dip between ambulatory awake and asleep SBP. In analyses that also considered sex, age, measures of body habitus and clinic blood pressure, left ventricle mass was related most closely to ambulatory awake SBP and relative left ventricular wall thickness was related most closely to ambulatory awake DBP (both P < 0.0005). CONCLUSIONS: Left ventricular geometric adaptations associated with an adverse prognosis were related more strongly to the level and variability of ambulatory blood pressure than theyh were to clinic blood pressure measurements, but were not associated with loss of the nocturnal dip in blood pressure.