Recombinant human serum amyloid P in healthy volunteers and patients with pulmonary fibrosis.

PRM-151, recombinant human Pentraxin-2 (PTX-2) also referred to as serum amyloid P (SAP), is under development for treatment of fibrosis. A First-in-Human (FIH) trial was performed to assess the safety, tolerability, and pharmacokinetics of single ascending intravenous doses of PRM-151 administered to healthy subjects, using a randomized, blinded, placebo controlled study design. Each cohort included three healthy subjects (PRM-151:placebo; 2:1). SAP levels were assessed using a validated ELISA method, non-discriminating between endogenous and exogenous SAP. At a dose level of 10 mg/kg, at which a physiologic plasma level of SAP was reached, two additional healthy volunteers and three pulmonary fibrosis (PF) patients were enrolled enabling comparison of the pharmacokinetic SAP profile between healthy volunteers and PF patients. In addition, the percentage of fibrocytes (CD45+/Procollagen-1+ cells) in whole blood samples was assessed to demonstrate biological activity of PRM-151 in the target population. PRM-151 administration was generally well tolerated. In two pulmonary fibrosis patients non-specific, transient skin reactions (urticaria and erythema) were observed. PRM-151 administration resulted in a 6-to 13-fold increase in mean baseline plasma SAP levels at dose levels of 5, 10, and 20 mg/kg. The estimated t1/2 of PRM-151 in healthy volunteers was 30 h. Pharmacokinetic profiles were comparable between healthy volunteers and PF patients. PRM-151 administration resulted in a 30-50% decrease in fibrocyte numbers 24 h post-dose. This suggests that administration of PRM-151 may be associated with a reduction of fibrocytes in PF patients, a population for which current pharmacotherapeutic options are limited. The pharmacological action of PRM-151 should be confirmed in future research.

Efficacy of the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine in women aged 15-25 years with and without serological evidence of previous exposure to HPV-16/18.

In the Phase III PATRICIA study (NCT00122681), the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine (Cervarix(®), GlaxoSmithKline Biologicals) was highly efficacious against HPV-16/18 infections and precancerous lesions in women HPV-16/18 deoxyribose nucleic acid (DNA) negative and seronegative at baseline. We present further data on vaccine efficacy (VE) against HPV-16/18 in the total vaccinated cohort including women who may have been exposed to HPV-16/18 infection before vaccination. In women with no evidence of current or previous HPV-16/18 infection (DNA negative and seronegative), VE was 90.3% (96.1% confidence interval: 87.3-92.6) against 6-month persistent infection (PI), 91.9% (84.6-96.2) against cervical intraepithelial neoplasia (CIN)1+ and 94.6% (86.3-98.4) against CIN2+ [97.7% (91.1-99.8) when using the HPV type assignment algorithm (TAA)]. In women HPV-16/18 DNA negative but with serological evidence of previous HPV-16/18 infection (seropositive), VE was 72.3% (53.0-84.5) against 6-month PI, 67.2% (10.9-89.9) against CIN1+, and 68.8% (-28.3-95.0) against CIN2+ [88.5% (10.8-99.8) when using TAA]. In women with no evidence of current HPV-16/18 infection (DNA negative), regardless of their baseline HPV-16/18 serological status, VE was 88.7% (85.7-91.1) against 6-month PI, 89.1% (81.6-94.0) against CIN1+ and 92.4% (84.0-97.0) against CIN2+ [97.0% (90.6-99.5) when using TAA]. In women who were DNA positive for one vaccine type, the vaccine was efficacious against the other vaccine type. The vaccine did not impact the outcome of HPV-16/18 infections present at the time of vaccination. Vaccination was generally well tolerated regardless of the woman's HPV-16/18 DNA or serological status at entry.

Sustained efficacy and immunogenicity of the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine: analysis of a randomised placebo-controlled trial up to 6.4 years.

BACKGROUND: Prophylactic human papillomavirus (HPV) vaccines have to provide sustained protection. We assessed efficacy, immunogenicity, and safety of the HPV-16/18 AS04-adjuvanted vaccine up to 6.4 years. METHODS: Women aged 15-25 years, with normal cervical cytology, who were HPV-16/18 seronegative and oncogenic HPV DNA-negative (14 types) at screening participated in a double-blind, randomised, placebo-controlled initial study (n=1113; 560 vaccine group vs 553 placebo group) and follow-up study (n=776; 393 vs 383). 27 sites in three countries participated in the follow-up study. Cervical samples were tested every 6 months for HPV DNA. Management of abnormal cytologies was prespecified, and HPV-16/18 antibody titres were assessed. The primary objective was to assess long-term vaccine efficacy in the prevention of incident cervical infection with HPV 16 or HPV 18, or both. We report the analyses up to 6.4 years of this follow-up study and combined with the initial study. For the primary endpoint, the efficacy analysis was done in the according-to-protocol (ATP) cohort; the analysis of cervical intraepithelial neoplasia grade 2 and above (CIN2+) was done in the total vaccinated cohort (TVC). The study is registered with ClinicalTrials.gov, number NCT00120848. FINDINGS: For the combined analysis of the initial and follow-up studies, the ATP efficacy cohort included 465 women in the vaccine group and 454 in the placebo group; the TVC included 560 women in the vaccine group and 553 in the placebo group. Vaccine efficacy against incident infection with HPV 16/18 was 95.3% (95% CI 87.4-98.7) and against 12-month persistent infection was 100% (81.8-100). Vaccine efficacy against CIN2+ was 100% (51.3-100) for lesions associated with HPV-16/18 and 71.9% (20.6-91.9) for lesions independent of HPV DNA. Antibody concentrations by ELISA remained 12-fold or more higher than after natural infection (both antigens). Safety outcomes were similar between groups: during the follow-up study, 30 (8%) participants reported a serious adverse event in the vaccine group versus 37 (10%) in the placebo group. None was judged related or possibly related to vaccination, and no deaths occurred. INTERPRETATION: Our findings show excellent long-term efficacy, high and sustained immunogenicity, and favourable safety of the HPV-16/18 AS04-adjuvanted vaccine up to 6.4 years. FUNDING: GlaxoSmithKline Biologicals (Belgium).

Dissolved organic matter in a tropical saline-alkaline lake of the East African Rift Valley.

Saline-alkaline lakes of the East African Rift are known to have an extremely high primary production supporting a potent carbon cycle. To date, a full description of carbon pools in these lakes is still missing. More specifically, there is not detailed information on the quality of dissolved organic matter (DOM), the main carbon energy source for heterotrophs prokaryotes. We report the first exhaustive description of DOM molecular properties in the water column of a meromictic saline-alkaline lake of the East African Rift. DOM availability, fate and origin were studied either quantitatively, in terms of dissolved organic carbon (DOC) and nitrogen (DON) or qualitatively, in terms of optical properties (absorbance) and molecular characterization of solid-phase extracted DOM (SPE-DOM) through negative electrospray ionization Fourier-transform ion cyclotron resonance mass spectrometry (FT-ICR-MS). DOM availability was high (DOC ∼ 8.1 mM in surface waters) and meromixis imprinted a severe quantitative and qualitative change on DOM pool. At the surface, DOM was rich in aliphatic and moderately in aromatic molecules and thus mirroring autochthonous microbial production together with photodegradation. At the bottom changes were extreme: DOC increased up to 5 times (up to 50 mM) and, molecular signature drifted to saturated, reduced and non-aromatic DOM suggesting intense microbial activity within organic sediments. At the chemocline, DOC was retained indicating that this interface is a highly reactive layer in terms of DOM processing. These findings underline that saline-alkaline lakes of the East African Rift are carbon processing hot spots and their investigation may broaden our understanding of carbon cycling in inland waters at large.

Ligula intestinalis (Cestoda: Diphyllobothriidae) in Kenya: a field investigation into host specificity and behavioural alterations.

Within the distribution of Ligula intestinalis, a tapeworm affecting freshwater fishes, there are genetically distinct and well-separated phylogenetic clusters. East Africa is represented by a single monophyletic clade which is understudied compared with Euro-Mediterranean clades. The present field investigation in the Lake Baringo and Naivasha catchments, Kenya, revealed that this L. intestinalis clade was highly host-specific, present in only 2 of 12 fishes examined; Barbus paludinosus in Naivasha and Barbus lineomaculatus in Baringo. In infected fish, cestodes comprised up to 20% of body weight. Only 1 parasite was recorded per fish, a contrast to infected fishes in Europe where mixed infections are commonplace. In B. lineomaculatus in Baringo, only fish of greater than 64 mm in length were parasitized. The highest parasite prevalence was recorded in fish of 70-77 mm in length, and reduced for lengths of 78-84 mm. Parasitized fish were significantly associated with a particular type of habitat, occurring most frequently in shallow littoral areas, and being absent from open water and rocky shore habitats. Uninfected fish were present in all habitats. This relationship between spatial occupancy and parasite prevalence is suggested to arise from behavioural alterations induced by the parasite that promotes completion of the parasite life cycle.

Letter: Feedback on abortion consultation.

PIP: The author agree's with C.M. Friedman's article ("Making Abortion Consultation Therapeutic," November 1973) that psychiatrists should stop prostituting themselves by claiming an abortion is necessary to safeguar d the woman's mental health. However, he feels the real human issue is whether a lift whould be destroyed simply because it is inconvenient for the mother and not, as Dr. Friedman suggests, because of "her mature longings for a child, her present capacity to love and give, her present reality, and a weighing of her morality."^ieng

Leukocytes in the cervix: a quantitative evaluation of cervicitis.

OBJECTIVE: To quantify the numbers of leukocytes in the normal cervix and relate these numbers to the diagnosis of cervicitis. METHODS: Isolated cell suspensions were prepared from cervical tissue recovered at hysterectomy from 37 women who had no obvious cervical disease. The percentages of CD45+ cells (leukocytes) in these preparations were determined using immunofluorescence-based flow cytometric analysis. These percentages were compared with the pathologist's assessment of cervicitis. RESULTS: Leukocytes were present in all cervical samples tested. For endocervical samples, the mean (+/- standard error of the mean [SEM]) percentage of CD45+ cells was 12.4 +/- 1.9% of cells in patients with a diagnosis of cervicitis (n = 16) and 9.1 +/- 1.1% in patients without cervicitis (n = 17). For ectocervical samples, the mean (+/- SEM) percentage was 14.8 +/- 3.0% in those with cervicitis (n = 16) and 9.5 +/- 1.6% in those without cervicitis (n = 19). The differences between samples from patients with cervicitis and those without cervicitis were not statistically significant at the .05 level. Intra- and interassay variabilities were 5.7 +/- 1.2% and 7.3 +/- 1.6%, respectively. CONCLUSION: Our study demonstrates there is a resident population of leukocytes in the cervix. Leukocyte number did not relate clearly and consistently to the diagnosis of cervicitis made by the pathologist. We suggest that the resident population of leukocytes, in the absence of other indicators of infection, may confuse determinations of cervicitis.

Analysis of acetic acid-induced whitening of high-grade squamous intraepithelial lesions.

Immature and dysplastic cervical squamous epithelium whitens after the application of acetic acid during a colposcopic examination. The whitening process occurs visually over several minutes and subjectively discriminates between dysplastic and normal tissue. In this work, examples of the acetowhitening process are detailed in three ways: the color-imaged colposcopic appearance of the acetowhitening of high-grade cervical intraepithelial neoplasia (CIN 2/3), the kinetics of these reflectance patterns transformed to reduce noise in the signal, and a self-normalized green to red ratio measurement of the kinetics of these reflectance patterns. A total of six patients with biopsy confirmed CIN 2/3 were examined to obtain a set of timed images tracking the acetowhitening and the whitening-decay process over the course of 5-10 min. Regions of normal mature squamous epithelium within the same patients were also followed as an internal control. We determined that the temporal change over a 10 min time period in the ratio of green to red light intensities, taken from the respective color channels of the CCD, provides a reliable measure to clearly distinguish CIN 2/3 from normal cervical epithelium. This imaging and data normalization procedure may be applied to cervical lesions of different grades, to determine if a quantitative estimate provides predictive value during the colposcopic diagnosis.

Elastin fibers resembling Sporothrix schenkii in the skin of a patient with acquired immunodeficiency syndrome.

We describe a patient with the acquired immunodeficiency syndrome who presented with an erythematous skin rash on his trunk and extremities. Initial histologic examination of a skin biopsy revealed silver-staining elements resembling Sporothrix schenkii. Additional histochemical and ultrastructural studies revealed that these elements were elastin fibers rather than fungi. The literature describing pseudofungal infections is reviewed.

Does comprehensive preventive medicine training enhance clinical prevention?

BACKGROUND AND OBJECTIVES: Clinical prevention is an important component of primary care, but its delivery remains deficient. This study determined the effect of a comprehensive preventive medicine curriculum, in combination with use of a prevention flow sheet, on community and family medicine residents' performance of 16 recommended clinical preventive services. METHODS: A retrospective study was done to document preventive services based on chart reviews of 240 clinic patients for the year prior to intervention initiation and the first year following the intervention. RESULTS: Chi-square analysis revealed a significant increase in the delivery of 12 out of 15 recommended clinical preventive services after the intervention. CONCLUSIONS: Implementation of comprehensive preventive medicine curricula, in combination with use of a clinical prevention flow sheet, is associated with an increase in preventive care offered to patients by community and family medicine residents.

Using stable isotope analyses to identify allochthonous inputs to Lake Naivasha mediated via the hippopotamus gut.

The hippopotamus grazes nocturnally on land and resides in water during the day. Much of the ingested material must therefore be defecated directly into the aquatic system and can thus be considered an allochthonous resource available to aquatic consumers. The utility of stable isotope analyses of carbon and nitrogen to distinguish hippo faecal matter from other potential basal resources was tested at Lake Naivasha, Kenya. Hippopotami proved faithful to a short grass diet although supplementary grazing of aquatic macrophytes was observed. The typical isotopic ratios of C4 grasses ingested were not altered substantially by gut processes, and were clearly distinct from algal and aquatic macrophyte isotopic ratios. However, marginal plants such as Cyperus papyrus exhibit C4 ratios, and so the technique is suitable only for use in localities where 'contamination' from such sources is negligible.

Paracervical block diminishes cramping associated with cryosurgery.

BACKGROUND: The choice of treatment method for cervical intraepithelial neoplasia can be dictated by the lesion size, by comfort of the operator with the technique, by the cost of the procedure, and by patient comfort with the procedure. The purpose of this research was to compare the usual method of cryosurgery (no anesthetic block) with a method using a paracervical block to reduce the pain and cramping associated with cryosurgery. METHODS: A prospective trial was designed and conducted in a colposcopy clinic. Of the 85 women enrolled in the study, all were immediately given 550 mg of naproxen sodium orally; 40 received no block and 45 received a paracervical block before the cryosurgery procedure. After the procedure, a trained interviewer elicited pain and cramping scores using a visual analog scale. Chi-square, Fisher's exact test, Mann-Whitney U, Wilcoxon signed-ranks test, Friedman's two-way analysis of variance, and multivariate analysis of variance with covariates were used to analyze the data. RESULTS: Each part of the double-freeze cryosurgical procedure was ranked according to the participants' perceptions of pain and cramping. The cramping after the first freeze was significantly less for women receiving the paracervical block than for the women undergoing the usual procedure (z = -2.44, P = .014). Including the discomfort from the injection itself, the women who received a paracervical block perceived less cramping overall during cryosurgery than the women with no block (z = -2.35, P = .019). The paracervical block did not decrease the pain from cryosurgery according to the participants' rankings of perceived pain. CONCLUSIONS: A paracervical block is effective in reducing the cramping from cryosurgery.

Pain and cramping associated with cryosurgery.

BACKGROUND: Many different cryosurgery methods have been described for the treatment of cervical intraepithelial neoplasia (CIN). The purpose of this study was to evaluate the pain and cramping perceived by patients undergoing four specific cryosurgical methods. METHODS: Seventy women consented to the prospective trial and were assigned to one of four cryosurgery techniques: a 2-minute double freeze, a 3-minute double freeze, a 5-minute single freeze, and a 5-minute double freeze. Immediately following the procedure, a trained interviewer recorded each woman's perceptions of pain and cramping. Age, parity, marital status, financial class, race or ethnicity, lesion severity, and pretreatment with a nonsteroidal anti-inflammatory drug (NSAID) were included in the analysis. RESULTS: The median pain scores for the 2-minute double freeze, the 3-minute double freeze, the 5-minute single freeze, and the 5-minute double freeze were 4, 3, 3, and 7, respectively, on a scale of 0 to 10. The median cramping scores for the procedures were 0, 0, 0, and 7, respectively. The median pain and cramping scores were significantly higher for the 5-minute double freeze than for any of the other procedures (P = .012 and P = < .001, respectively). CONCLUSIONS: Pain and cramping are associated with cryosurgery, but the 5-minute double freeze caused the most pain and cramping of all the cryosurgery methods tested. Pretreatment with an NSAID did not lessen the cramping or pain perceived during the 5-minute double freeze.

Cervical mucosal block effectively reduces the pain and cramping from cryosurgery.

BACKGROUND: Cryosurgery is an effective treatment for squamous intraepithelial lesions, but causes pain and cramping regardless of the particular method of cryosurgery used. The purpose of our study was to determine how effective a four-quadrant cervical mucosal block is in reducing the pain and cramping of cryosurgery. METHODS: Of the 112 women presenting for cryosurgery at the teaching clinics of the University of Missouri-Kansas City School of Medicine at Truman Medical Center-East between September 1995 and September 1996, 87 completed the study. The first 39 women were given the standard treatment of no block with the cryosurgery procedure. The subsequent 48 women were given a four-quadrant submucosal block of 1% lidocaine with 1:100,000 epinephrine 5 minutes before cryosurgery. The intensity of pain and cramping of each part of the procedure was measured on 100-mm visual analog scales. RESULTS: The pain and cramping of cryosurgery were significantly reduced (P < .05) with the mucosal block for all measured parts of the cryosurgery procedure, including pain of the first freeze (39 mm vs 12 mm), cramping of the first freeze (49 mm vs 13 mm), pain of the second freeze (24 mm vs 12 mm), cramping of the second freeze (32 mm vs 18 mm), pain of the total composite procedure (44 mm vs 28 mm), and cramping of the total composite procedure (51 mm vs 21 mm). CONCLUSIONS: A four-quadrant mucosal block effectively reduces the amount of pain and cramping associated with cryosurgery.

Principles of nonstress testing in pregnancy.

The nonstress test has been used to document second and third trimester fetal well-being for the past 40 years. It serves as a surrogate measure of the developing fetal autonomic nervous system. The nonstress test is more specific than sensitive, thus being a better indicator of fetal health than fetal illness. The test itself is read as reactive or nonreactive and may be repeated at intervals as a screen for high-risk maternal conditions.

Cervical intraepithelial neoplasia in pregnancy.

There is no evidence that cervical intraepithelial neoplasia (CIN) progresses more rapidly because of pregnancy. Management of CIN in pregnancy, therefore, is conservative. Screening for invasive cancer is done at the first prenatal visit. Colposcopically directed biopsy can then be used to rule out invasive cancer. Postpartum cytology and colposcopy are important follow-up procedures for these women. Cryosurgery for CIN is usually contraindicated in pregnancy. This report includes examples of two pregnant patients with high-grade lesions. A diagnostic and treatment algorithm based on the current "expert opinion"is presented.

Is it cost-effective to use a mucosal or paracervical block to relieve the pain and cramping from cryosurgery? A decision model.

BACKGROUND: Cryosurgery is an effective treatment for cervical intraepithelial neoplasia, but it often causes pain and cramping. Both paracervical and mucosal blocks have been shown to provide relief from the pain and cramping associated with cryosurgery. The purpose of this article is to recommend the use of mucosal block, paracervical block, or no block on the basis of which procedure minimizes the costs of averting the pain and cramping that a woman experiences during cryosurgery. METHODS: A decision model was constructed encompassing the options (mucosal block, paracervical block, or no block) that a physician has when performing cryosurgery. The 4 possible outcomes for a patient undergoing cryosurgery were diagrammed as: (1) no pain and no cramping; (2) only cramping; (3) only pain; and (4) both pain and cramping. Each of these outcomes was measured on a 200-mm horizontal visual analog scale. Costs were derived for cryosurgery from the office perspective. Sensitivity analyses were conducted to test the robustness of the analysis. RESULTS: The base case analysis showed that the lowest cost per pain and cramping averted was for women who had a mucosal block before cryosurgery ($153.87), compared with women with a paracervical block ($183.24) and women with no block ($218.83). CONCLUSIONS: A mucosal block is the most cost-effective method to avert the pain and cramping from cryosurgery in women who have taken a nonsteroidal anti-inflammatory drug before the procedure.

Anesthetic blocks for loop electrosurgical excision procedure.

BACKGROUND: Various types of anesthetic blocks have been used to prevent pain during ambulatory gynecologic surgery. The purpose of this study was to compare the pain and cramping perceived by patients during the loop electrosurgical excision procedure when intramucosal or distal paracervical blocks were used. METHODS: Seventy-seven women consented to participate in the prospective clinical trial. All women were premedicated with a nonsteroidal anti-inflammatory drug. Immediately after the procedure, a trained interviewer, blinded to the type of anesthetic block, recorded the patient's perceptions of pain and cramping caused by the procedure. Age, parity, marital status, lesion severity, loop size used, number of specimens, amount of bleeding, method of hemostasis, and thermal artifact were included on the analysis. RESULTS: On a Likert scale in which 0 = no pain/cramping and 10 = worst pain/cramping, the median pain score was 3 for the distal paracervical block and 4 for the intramucosal block. The median cramping scores were 3 and 2, respectively. Pain and cramping scores did not differ significantly between the two block cohorts. The demographic and procedural variables did not predict the perception of pain or cramping. Most (89.6%) of the study population experienced pain, whereas fewer (64.9%) experienced cramping. Subjects reported significantly less cramping than pain, irrespective of the anesthetic block used (chi 2 = 13.35, P = .0003). CONCLUSIONS: There is no difference in the perceptions of pain and cramping resulting from the loop electrosurgical excision procedure between patients receiving an intramucosal block and those receiving a distal paracervical block. There is minimal pain and cramping associated with the procedure.

Collection devices for human papillomavirus.

BACKGROUND: Human papillomavirus (HPV) testing has relied to date on samples collected by experienced health professionals. Self-administered testing devices could allow HPV testing to occur in large-scale epidemiologic studies of primary care screening populations. The purpose of this study is to determine whether a self-collection device for cervicovaginal HPV infection could be developed. METHODS: A prospective randomized trial of a consecutive sampling of 93 women, 18 years or older, receiving routine cervical cancer screening and colposcopy in the urban gynecologic clinics in Philadelphia, Pennsylvania, were randomized into 2 arms. Women in arm 1 used a self-administered tampon before the physician-directed swabs of the cervix; in arm 2, women underwent the physician-directed swab testing before using the self-administered tampon. The concordance of HPV DNA positivity between sampling methods detected by a Hybrid Capture HPV tube test for both low- and high-risk types of HPV was the main outcome measure. RESULTS: The concordance rate (ie, women whose cultures were classified as negative on both tests or positive on both tests) for arms 1 and 2 were similar: 78.3% and 80.9%, respectively. CONCLUSIONS: The tampon was equivalent to the physician-directed swab in HPV detection and suggests its feasibility in long-term primary care studies of screening populations.

Healing experiences after cervical cryosurgery.

BACKGROUND: Treatment for cervical intraepithelial neoplasia with cryosurgery is uncomfortable for many women. The subsequent healing process is also thought to bring discomfort. The purpose of our study was to describe women's experiences after cryosurgery, and how obesity, age, and gravidity affected, the healing process. METHODS: We developed a survey from focus group results to measure the unpleasantness of hydrorrhea (watery discharge) from cryosurgery, the pad protection required, and the odor associated with the hydrorrhea. The cryosurgical experiences were compared with normal menses for the use and frequency of pad protection, medications used, and any activity restrictions. RESULTS: Cryosurgical experiences were unpleasant for 78.3% of the women because of the pain and cramping of the procedure and the resulting hydrorrhea, odor, and necessity of wearing pads for protection. These experiences after cryosurgery caused 38.6% to restrict their activities and 67.1% to take medications, a significantly greater proportion than the 16.9% whose activities were restricted normal menses and the 26.8% who took medications for normal menses (P=-.004, P <.001, respectively). In addition to these experiences, obese, multigravid, and older women were more bothered by the duration of wearing pads than their counterparts (P=.0246, =.0061, and P=.0159, respectively). CONCLUSIONS: Our study showed that the cryosurgical healing process was not pleasant, and was least tolerable for obese, multigravid, and older women. As many as 50% of women undergoing cryosurgery will perceive the hydrorrhea, its odor, and the wearing of pads to be worse than normal menses, especially if their menses are usually light.