The Herbal Alternatives for Menopause (HALT) Study: background and study design

We designed a randomized double-blind randomized trial to examine the short and long-term effects of alternative approaches commonly used to manage menopause symptoms. Women were randomly assigned to: (1) black cohosh 160 mg daily; (2) multibotanical (50 mg black cohosh, alfalfa, chaste tree, dong quai, false unicorn, licorice, oats, pomegranate, Siberian ginseng, boron) four capsules daily; (3) multibotanical plus telephone counseling to increase dietary soy; (4) conjugated equine estrogen 0.625 mg +/- 2.5 mg medroxyprogesterone acetate; or (5) placebo. Working with a skilled CAM provider helped us choose interventions that reflected naturopathic practices worthy of study. Mass mailing, with careful tracking and rapid responses to recruitment rates, was an effective and cost-effective recruitment strategy. Creativity was necessary to construct methods for blinding capsules and the dietary soy intervention. Independent testing of herbal products was vital to confirming their constituents. The Data and Safety and Monitoring Committee, and project officers at the funding agency, were critical partners in designing responses to unanticipated Women's Health Initiative findings published during the HALT trial. Careful monitoring of adverse events may provide much needed information about side effects of herbal products and supplements. Despite inherent challenges, the study of alternative therapies for menopause symptoms is a rewarding and important area deserving of further inquiry.     

The incidence of, risk factors for, and sequelae of herpes zoster among HIV patients in the highly active antiretroviral therapy era

BACKGROUND: Whereas the incidence, risk factors, and clinical sequelae of herpes zoster have been studied in the general population and in HIV patients in the era before highly active antiretroviral therapy (HAART), they have yet to be fully understood in the current era of HAART. METHODS: We conducted a retrospective cohort study of patients enrolled in an urban HIV clinic between January 1, 1997 and December 31, 2001. Patients with an episode of herpes zoster during this period were identified, and their charts were reviewed. A nested case-control analysis was used to assess factors associated with an initial episode of herpes zoster. Multivariate conditional logistic regression analyses were used to assess risk factors for zoster. Logistic regression was performed to assess factors associated with complicated zoster. RESULTS: Two hundred eighty-two episodes of herpes zoster were identified in 239 patients. Of these episodes, 158 were new occurrences of zoster and 124 were recurrent zoster events. The incidence of zoster during the study period was 3.2 per 100 person-years of follow-up. The incident cases reflected the clinic population, with most patients being male (63%) and African American (77%) and having injection drug use as their HIV risk factor (49%). The mean age of the patients was 41 years. Sixty-seven percent of patients had single dermatomal involvement, and the thorax was involved in 41%. In multivariate regression, being on HAART (odds ratio [OR] = 2.39, 95% confidence interval [CI]: 1.65 to 3.49) and a CD4 count of 50 to 200 cells/mm (OR = 2.69, 95% CI: 1.44 to 5.01) compared with a CD4 count less than 50 cells/mm were associated with an increased risk of zoster. Twenty-eight patients (18%) developed post-herpetic neuralgia (PHN), and 29 patients (18%) had other complications. Male-to-male sex as an HIV risk factor (P = 0.02) and being on HAART at a zoster episode (P = 0.03) were protective against complicated zoster. CONCLUSIONS: Our results suggest that zoster infection rates have not changed in the current HAART era but that a significant percentage of patients develop complications, particularly PHN, which is quite remarkable considering the young age of our population.     

Modulation of osteopontin in proteinuria-induced renal interstitial fibrosis

Proteinuria is associated with macrophage-dependent interstitial fibrosis (IF). Osteopontin (OPN), a macrophage chemoattractant, may be involved in the transition of proteinuria to IF but protective properties have also been reported. To elucidate whether OPN may be involved in the proteinuria-induced cascade of tubulointerstitial damage, renal expression of OPN was studied during the development of proteinuria-induced renal damage and during anti-proteinuric intervention with ACE inhibition (ACEi). First, the temporal relationships between proteinuria, interstitial OPN induction, and IF in adriamycin nephrosis (AN), a model of chronic proteinuria-induced renal damage, were studied. Second, the effect of anti-proteinuric treatment on OPN expression was investigated. The time course of OPN induction and markers of renal damage was studied in rats with unilateral AN at 6-week intervals until week 30. In a second study, a renal biopsy was taken 6 weeks after induction of bilateral AN; subsequently, rats were treated with ACEi until termination (week 12). In unilateral AN, proteinuria developed gradually and stabilized at week 10. In proteinuric kidneys, OPN expression was induced from week 12 onwards. Simultaneously, a progressive increase in interstitial macrophages, alpha-smooth muscle actin (alpha-SMA), collagen type III, and focal glomerulosclerosis (FGS) was observed. In bilateral AN, ACEi reduced proteinuria and OPN protein and stabilized fibrosis. In untreated animals, OPN mRNA increased, with stable OPN protein and fibrosis and increased FGS. Thus, in AN, development of proteinuria is followed by up-regulation of OPN along with markers of renal damage. The up-regulation of OPN is reversible by anti-proteinuric treatment without a corresponding reduction in fibrosis. Whereas these data are consistent with a role for OPN in the cascade of transition from proteinuria to fibrosis, intervention with ACEi showed that reduction of OPN does not attenuate established fibrosis.     

Effects of 2 ankle fatigue models on the duration of postural stability dysfunction

Context: Muscle fatigue is generally categorized in 2 ways: that caused by peripheral weakness (peripheral fatigue) and that caused by a progressive failure of voluntary neural drive (central fatigue). Numerous variables have been studied in conjunction with fatigue protocols, including postural stability, maximum voluntary contraction force, and reaction time. When torque recordings fall below 50% of a maximum voluntary contraction, the muscle is described as fatigued, but whether this value is a good indicator of fatigue has not been studied.Objective: To compare the effects of 2 ankle musculature fatigue protocols (30% and 50%) on the duration of postural stability dysfunction.Design: To assess differences between the 30% and 50% fatigue protocols, we calculated a 1 between-groups factor (subjects) and 2 within-groups factors (fatigue, test) analysis of variance.Setting: E.J. Nutter Athletic Training Facility.Patients or Other Participants: Twenty subjects (10 men, 10 women; age = 21.15 ± 2.23 years; height = 172.97 ± 9.86 cm; mass = 70.62 ± 14.60 kg) volunteered for this study. Subjects had no history of lower extremity injury, vestibular or balance disorders, functional ankle instability, or head injury in the past 6 months.Intervention(s): On separate days, subjects performed isokinetic fatiguing contractions of the plantar flexors and dorsiflexors in a 30% protocol (70% decrease in strength) and a 50% protocol (50% decrease in strength).Main Outcome Measure(s): Baseline and postfatigue postural stability scores were determined before and after the isokinetic fatiguing contractions. Plantar-flexion peak-torque measurements were obtained for the 2 fatiguing protocols. Three prefatigue and 12 postfatigue postural stability trials were recorded. Velocities for testing were 60°/s for plantar flexion and 120°/s for dorsiflexion.Results: Sway velocity was significantly greater when the ankle was fatigued to 30% (1.56°/s) than in the 50% condition (1.36°/s). For the 30% protocol, sway was significantly impaired when the pretest condition (1.19°/s) was compared with posttest trial 1 (2.34°/s), trial 2 (2.37°/s), and trial 3 (1.71°/s). For the 50% protocol, sway was significantly impaired when the pretest condition (1.27°/s) was compared with posttest trial 1 (2.02°/s).Conclusions: The 30% fatigue protocol resulted in significantly longer impairment of postural stability than the 50% protocol. Because the 30% protocol resulted in a greater effect but was relatively short-lived (approximately 75 to 90 s), it is more useful for research purposes.     

Determinants of the competing outcomes of intrauterine infection,abruption, or spontaneous preterm birth after preterm premature rupture of membranes*

Objective: Patients with PPROM are at risk for a variety of outcomes, including chorioamnionitis (CA), placental abruption (PA), or preterm labor (PTL). Competing risk regression can analyze a cohort’s risk of individual outcomes while accounting for ongoing deliveries secondary to competing events.

Methods: A secondary analysis of the subjects from MFMU BEAM study of neuroprotection after preterm birth (BEAM) with conservative PPROM management. Deliveries were categorized as: PA, CA, PTL, “elective” or “indicated”. The association between outcomes of PA, CA or PTL and clinical predictors of twins, ethnicity, parity, gestational age at rupture, bleeding, contractions, cervical dilation, preterm birth history, weight, and genitourinary infections were evaluated via competing risk regression.

Result: 1970 subjects were included. The significance and directionality of predictors varied according to specific outcomes. Patients with twins had an increased PTL hazard (1.85) though reductions in CA- (0.66) or PA-specific (0.56) hazards. Decreased latency in African-Americans was almost entirely due to an increased CA hazard (1.44) without a significant association with PTL. Increasing gestational age at membrane rupture was associated with a decreasing hazard of CA although increasing hazard of PTL.

Conclusions: For patients with PPROM, the hazards associated with different clinical predictors vary according to exact outcomes.     

Cervical length,risk factors,and delivery outcomes among women with spontaneous preterm birth

Objectives: To evaluate differences in risk factors and delivery outcomes among women with spontaneous preterm birth (sPTB) with short (≤25?mm) versus normal (>25?mm) cervical length (CL).

Methods: Secondary analysis of a prospective cohort study of singleton gestations between 18 0/7 and 23 6/7 weeks, without prior sPTB, undergoing universal transvaginal CL screening between 1 January 2012 and 31 December 2013. Only women with sPTB (<37 0/7 weeks) were included. Demographic characteristics, risk factors for sPTB, delivery outcomes and presentation of PTB were collected. The primary outcome was mean number of risk factors.

Results: The cohort included 2071 women, of which 145 (7%) had PTB and 84 (4%) had sPTB. Sixty-nine (82%) women with sPTB had a CL >25?mm and 15 (18%) had a CL≤25?mm. Women with a short CL did not differ from women with normal CL with respect to demographic variables or mean number of risk factors (4.20?±?2.11 versus 3.52?±?1.97, p?=?0.23), but they did deliver at a significantly earlier gestational age (25.0?±?1.1 versus 34.6?±?3.1 weeks, p?<?0.01). The distribution of the presentation of sPTB was different in women with a short versus normal CL (p?<?0.01).

Conclusions: Among women with sPTB, women with a short CL had similar number of risk factors, but were more likely to deliver at a significantly earlier gestational age. A short CL identifies women at risk for very early sPTB.     

Cesarean delivery complications in women with morbid obesity

Objective: To compare cesarean complication rates between women with body mass index (BMI) 40–49.9?kg/m² and BMI?≥?50?kg/m² and associations with surgical techniques.

Methods: This retrospective cohort study from 2009 to 2014 included women who underwent cesarean with delivery BMI?≥?50 and an equal number with BMI 40–49.9. Wound infections and/or separations were compared. We also examined wound complication rates between skin closure techniques and self-retaining retractor use.

Results: Among 498 patients (249 with BMI?≥?50 and 249 with BMI 40–49.9) there were no differences in estimated blood loss >1000?mL, blood transfusion, deep vein thrombosis or endometritis. Among those with outpatient follow-up (144 with BMI?≥?50 and 162 with BMI 40–49.9), those with BMI?≥?50 had a significantly higher rate of wound separations (p?=?0.01) but not infections. There were no differences in wound complication rates between skin closure techniques or self-retaining retractor use, though the study was not powered for these comparisons.

Conclusion: Wound complications, particularly separations, increase with BMI?≥?50 compared to a lesser degree of morbid obesity. Skin closure techniques and self-retaining retractor use were not associated with cesarean wound complications in patients with morbid obesity.     

Oral delivery of BCG Moreau Rio de Janeiro gives equivalent protection against tuberculosis but with reduced pathology compared to parenteral BCG Danish vaccination

There is a need for an improved vaccine to better control human tuberculosis (TB), as the only currently available TB vaccine, bacillus Calmette–Guerin (BCG) delivered parenterally, offers variable levels of efficacy. Therefore, recombinant strains expressing additional antigens are being developed alongside alternative routes to parenteral delivery. There is strong evidence that BCG Moreau (RdJ) is a safe and effective vaccine in humans when given by the oral route. This study compared the efficacy of a single oral dose of wild type BCG Moreau Rio de Janeiro (RdJ), or a recombinant RdJ strain expressing Ag85B-ESAT6 fusion protein, formulated with and without lipid to enhance oral delivery, with subcutaneous BCG Danish 1331 and saline control groups in a guinea pig aerosol infection model of pulmonary tuberculosis. Protection was measured as survival at 30 weeks post-challenge and reduced bacterial load and histopathology in lungs and spleen. Results showed that a single oral dose of BCG Moreau (RdJ) or recombinant BCG Moreau (RdJ)-Ag85B-ESAT6, formulated with or without lipid, gave protection equivalent to subcutaneously delivered BCG Danish in the 30 weeks post-challenge survival study. The orally delivered vaccines gave reduced pathology scores in the lungs (three of the four formulations) and spleens (all four formulations) compared to subcutaneously delivered BCG Danish. The oral wild type BCG Moreau (RdJ) in lipid and the unformulated oral wild type BCG Moreau (RdJ) vaccine also gave statistically lower bacterial loads in the lungs and spleens, respectively, compared to subcutaneously delivered BCG Danish. This study provides further evidence to show that lipid formulation does not impair vaccine efficacy and may enhance the delivery and stability of oral vaccines intended for use in countries with poor health infrastructure. Oral delivery also avoids needles (and associated cross-infection risks) and immunisation without the need for specially trained medical professional staff.     

Research paradigms in medical education research

Medical Education 2010: 44 : 358–366 Context The growing popularity of less familiar methodologies in medical education research, and the use of related data collection methods, has made it timely to revisit some basic assumptions regarding knowledge and evidence. Methods This paper outlines four major research paradigms and examines the methodological questions that underpin the development of knowledge through medical education research. Discussion This paper explores the rationale behind different research designs, and shows how the underlying research philosophy of a study can directly influence what is captured and reported. It also explores the interpretivist perspective in some depth to show how less familiar paradigm perspectives can provide useful insights to the complex questions generated by modern healthcare practice. Conclusions This paper concludes that the quality of research is defined by the integrity and transparency of the research philosophy and methods, rather than the superiority of any one paradigm. By demonstrating that different methodological approaches deliberately include and exclude different types of data, this paper highlights how competing knowledge philosophies have practical implications for the findings of a study.