Ultra-radical (extensive) surgery versus standard surgery for the primary cytoreduction of advanced epithelial ovarian cancer.

BACKGROUND: Ovarian cancer is the seventh most common cancer among women and the leading cause of death in women with gynaecological malignancies. Opinions differ regarding the role of ultra-radical (extensive) cytoreductive surgery in ovarian cancer treatment. OBJECTIVES: To evaluate the effectiveness and morbidity associated with ultra-radical/extensive surgery in the management of advanced-stage epithelial ovarian cancer. SEARCH METHODS: We searched CENTRAL (2021, Issue 11), MEDLINE Ovid and Embase Ovid up to November 2021. We also searched registers of clinical trials, abstracts of scientific meetings, reference lists of included studies and contacted experts in the field. SELECTION CRITERIA: Randomised controlled trials (RCTs) or non-randomised studies (NRS), analysed using multivariate methods, that compared ultra-radical/extensive and standard surgery in women with advanced primary epithelial ovarian cancer. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed whether potentially relevant studies met the inclusion criteria, abstracted data and assessed the risk of bias. We identified three NRS and conducted meta-analyses where possible. MAIN RESULTS: We identified three retrospective observational studies for inclusion in the review. Two studies included women exclusively undergoing upfront primary debulking surgery (PDS) and the other study including both PDS and interval debulking surgical (IDS) procedures. All studies were at critical risk of bias due to retrospective and non-randomised study designs. Meta-analysis of two studies, assessing 397 participants, found that women who underwent radical procedures, as part of PDS, may have a lower risk of mortality compared to women who underwent standard surgery (adjusted HR 0.60, 95% CI 0.43 to 0.82; I2 = 0%; very low-certainty evidence), but the evidence is very uncertain. The results were robust to a sensitivity analysis including women with more-extensive disease (carcinomatosis) (adjusted HR 0.61, 95% CI 0.44 to 0.85; I2 = 0%; n = 283, very low-certainty evidence), but the evidence is very uncertain. One study reported a comparison of radical versus standard surgical procedures associated with both PDS and IDS procedures, but a multivariate analysis was only undertaken for disease-free survival (DFS) and therefore the certainty of the evidence was not assessable for overall survival (OS) and remains very low. The lack of reporting of OS meant the study was at high risk of bias for selective reporting of outcomes. One study, 203 participants, found that women who underwent radical procedures as part of PDS may have a lower risk of disease progression or death compared to women who underwent standard surgery (adjusted HR 0.62, 95% CI 0.42 to 0.92; very low-certainty evidence), but the evidence is very uncertain. The results were robust to a sensitivity analysis in one study including women with carcinomatosis (adjusted HR 0.52, 95% CI 0.33 to 0.82; n = 139; very low-certainty evidence), but the evidence is very uncertain. A combined analysis in one study found that women who underwent radical procedures (using both PDS and IDS) may have an increased chance of disease progression or death than those who received standard surgery (adjusted HR 1.60, 95% CI 1.11 to 2.31; I2 = 0%; n = 527; very low-certainty evidence), but the evidence is very uncertain. In absolute and unadjusted terms, the DFS was 19.3 months in the standard surgery group, 15.8 in the PDS group and 15.9 months in the IDS group. All studies were at critical risk of bias and we only identified very low-certainty evidence for all outcomes reported in the review. Perioperative mortality, adverse events and quality of life (QoL) outcomes were either not reported or inadequately reported in the included studies. Two studies reported perioperative mortality (death within 30 days of surgery), but they did not use any statistical adjustment. In total, there were only four deaths within 30 days of surgery in both studies. All were observed in the standard surgery group, but we did not report a risk ratio (RR) to avoid potentially misleading results with so few deaths and very low-certainty evidence. Similarly, one study reported postoperative morbidity, but the authors did not use any statistical adjustment. Postoperative morbidity occurred more commonly in women who received ultra-radical surgery compared to standard surgery, but the certainty of the evidence was very low. AUTHORS' CONCLUSIONS: We found only very low-certainty evidence comparing ultra-radical surgery and standard surgery in women with advanced ovarian cancer. The evidence was limited to retrospective, NRSs and so is at critical risk of bias. The results may suggest that ultra-radical surgery could result in improved OS, but results are based on very few women who were chosen to undergo each intervention, rather than a randomised study and intention-to-treat analysis, and so the evidence is very uncertain. Results for progression/DFS were inconsistent and evidence was sparse. QoL and morbidity was incompletely or not reported in the three included studies. A separate prognostic review assessing residual disease as a prognostic factor in this area has been addressed elsewhere, which demonstrates the prognostic effect of macroscopic debulking to no macroscopic residual disease. In order to aid existing guidelines, the role of ultra-radical surgery in the management of advanced-stage ovarian cancer could be addressed through the conduct of a sufficiently powered, RCT comparing ultra-radical and standard surgery, or well-designed NRSs, if this is not possible.

Impact of residual disease as a prognostic factor for survival in women with advanced epithelial ovarian cancer after primary surgery.

BACKGROUND: Ovarian cancer is the seventh most common cancer among women and a leading cause of death from gynaecological malignancies. Epithelial ovarian cancer is the most common type, accounting for around 90% of all ovarian cancers. This specific type of ovarian cancer starts in the surface layer covering the ovary or lining of the fallopian tube. Surgery is performed either before chemotherapy (upfront or primary debulking surgery (PDS)) or in the middle of a course of treatment with chemotherapy (neoadjuvant chemotherapy (NACT) and interval debulking surgery (IDS)), with the aim of removing all visible tumour and achieving no macroscopic residual disease (NMRD). The aim of this review is to investigate the prognostic impact of size of residual disease nodules (RD) in women who received upfront or interval cytoreductive surgery for advanced (stage III and IV) epithelial ovarian cancer (EOC). OBJECTIVES: To assess the prognostic impact of residual disease after primary surgery on survival outcomes for advanced (stage III and IV) epithelial ovarian cancer. In separate analyses, primary surgery included both upfront primary debulking surgery (PDS) followed by adjuvant chemotherapy and neoadjuvant chemotherapy followed by interval debulking surgery (IDS). Each residual disease threshold is considered as a separate prognostic factor. SEARCH METHODS: We searched CENTRAL (2021, Issue 8), MEDLINE via Ovid (to 30 August 2021) and Embase via Ovid (to 30 August 2021). SELECTION CRITERIA: We included survival data from studies of at least 100 women with advanced EOC after primary surgery. Residual disease was assessed as a prognostic factor in multivariate prognostic models. We excluded studies that reported fewer than 100 women, women with concurrent malignancies or studies that only reported unadjusted results. Women were included into two distinct groups: those who received PDS followed by platinum-based chemotherapy and those who received IDS, analysed separately. We included studies that reported all RD thresholds after surgery, but the main thresholds of interest were microscopic RD (labelled NMRD), RD 0.1 cm to 1 cm (small-volume residual disease (SVRD)) and RD > 1 cm (large-volume residual disease (LVRD)). DATA COLLECTION AND ANALYSIS: Two review authors independently abstracted data and assessed risk of bias. Where possible, we synthesised the data in meta-analysis. To assess the adequacy of adjustment factors used in multivariate Cox models, we used the 'adjustment for other prognostic factors' and 'statistical analysis and reporting' domains of the quality in prognosis studies (QUIPS) tool. We also made judgements about the certainty of the evidence for each outcome in the main comparisons, using GRADE. We examined differences between FIGO stages III and IV for different thresholds of RD after primary surgery. We considered factors such as age, grade, length of follow-up, type and experience of surgeon, and type of surgery in the interpretation of any heterogeneity. We also performed sensitivity analyses that distinguished between studies that included NMRD in RD categories of < 1 cm and those that did not. This was applicable to comparisons involving RD < 1 cm with the exception of RD < 1 cm versus NMRD. We evaluated women undergoing PDS and IDS in separate analyses. MAIN RESULTS: We found 46 studies reporting multivariate prognostic analyses, including RD as a prognostic factor, which met our inclusion criteria: 22,376 women who underwent PDS and 3697 who underwent IDS, all with varying levels of RD. While we identified a range of different RD thresholds, we mainly report on comparisons that are the focus of a key area of clinical uncertainty (involving NMRD, SVRD and LVRD). The comparison involving any visible disease (RD > 0 cm) and NMRD was also important. SVRD versus NMRD in a PDS setting In PDS studies, most showed an increased risk of death in all RD groups when those with macroscopic RD (MRD) were compared to NMRD. Women who had SVRD after PDS had more than twice the risk of death compared to women with NMRD (hazard ratio (HR) 2.03, 95% confidence interval (CI) 1.80 to 2.29; I2 = 50%; 17 studies; 9404 participants; moderate-certainty). The analysis of progression-free survival found that women who had SVRD after PDS had nearly twice the risk of death compared to women with NMRD (HR 1.88, 95% CI 1.63 to 2.16; I2 = 63%; 10 studies; 6596 participants; moderate-certainty). LVRD versus SVRD in a PDS setting When we compared LVRD versus SVRD following surgery, the estimates were attenuated compared to NMRD comparisons. All analyses showed an overall survival benefit in women who had RD < 1 cm after surgery (HR 1.22, 95% CI 1.13 to 1.32; I2 = 0%; 5 studies; 6000 participants; moderate-certainty). The results were robust to analyses of progression-free survival. SVRD and LVRD versus NMRD in an IDS setting The one study that defined the categories as NMRD, SVRD and LVRD showed that women who had SVRD and LVRD after IDS had more than twice the risk of death compared to women who had NMRD (HR 2.09, 95% CI 1.20 to 3.66; 310 participants; I2 = 56%, and HR 2.23, 95% CI 1.49 to 3.34; 343 participants; I2 = 35%; very low-certainty, for SVRD versus NMRD and LVRD versus NMRD, respectively). LVRD versus SVRD + NMRD in an IDS setting Meta-analysis found that women who had LVRD had a greater risk of death and disease progression compared to women who had either SVRD or NMRD (HR 1.60, 95% CI 1.21 to 2.11; 6 studies; 1572 participants; I2 = 58% for overall survival and HR 1.76, 95% CI 1.23 to 2.52; 1145 participants; I2 = 60% for progression-free survival; very low-certainty). However, this result is biased as in all but one study it was not possible to distinguish NMRD within the < 1 cm thresholds. Only one study separated NMRD from SVRD; all others included NMRD in the SVRD group, which may create bias when comparing with LVRD, making interpretation challenging. MRD versus NMRD in an IDS setting Women who had any amount of MRD after IDS had more than twice the risk of death compared to women with NMRD (HR 2.11, 95% CI 1.35 to 3.29, I2 = 81%; 906 participants; very low-certainty). AUTHORS' CONCLUSIONS: In a PDS setting, there is moderate-certainty evidence that the amount of RD after primary surgery is a prognostic factor for overall and progression-free survival in women with advanced ovarian cancer. We separated our analysis into three distinct categories for the survival outcome including NMRD, SVRD and LVRD. After IDS, there may be only two categories required, although this is based on very low-certainty evidence, as all but one study included NMRD in the SVRD category. The one study that separated NMRD from SVRD showed no improved survival outcome in the SVRD category, compared to LVRD. Further low-certainty evidence also supported restricting to two categories, where women who had any amount of MRD after IDS had a significantly greater risk of death compared to women with NMRD. Therefore, the evidence presented in this review cannot conclude that using three categories applies in an IDS setting (very low-certainty evidence), as was supported for PDS (which has convincing moderate-certainty evidence).

Mycobacterium tuberculosis subverts negative regulatory pathways in human macrophages to drive immunopathology.

Tuberculosis remains a global pandemic and drives lung matrix destruction to transmit. Whilst pathways driving inflammatory responses in macrophages have been relatively well described, negative regulatory pathways are less well defined. We hypothesised that Mycobacterium tuberculosis (Mtb) specifically targets negative regulatory pathways to augment immunopathology. Inhibition of signalling through the PI3K/AKT/mTORC1 pathway increased matrix metalloproteinase-1 (MMP-1) gene expression and secretion, a collagenase central to TB pathogenesis, and multiple pro-inflammatory cytokines. In patients with confirmed pulmonary TB, PI3Kδ expression was absent within granulomas. Furthermore, Mtb infection suppressed PI3Kδ gene expression in macrophages. Interestingly, inhibition of the MNK pathway, downstream of pro-inflammatory p38 and ERK MAPKs, also increased MMP-1 secretion, whilst suppressing secretion of TH1 cytokines. Cross-talk between the PI3K and MNK pathways was demonstrated at the level of eIF4E phosphorylation. Mtb globally suppressed the MMP-inhibitory pathways in macrophages, reducing levels of mRNAs encoding PI3Kδ, mTORC-1 and MNK-1 via upregulation of miRNAs. Therefore, Mtb disrupts negative regulatory pathways at multiple levels in macrophages to drive a tissue-destructive phenotype that facilitates transmission.

Full-length genome characterization of HIV type 1 subtype C isolates from two slow-progressing perinatally infected siblings in South Africa.

Isolation and characterization of HIV-1 from asymptomatic, slow-progressing individuals are important in studying viral pathogenesis and facilitate the development of vaccines and antivirals. In this study we identified two slow-progressing HIV-1-infected siblings, isolated viruses, and sequenced the full-length genome, to identify virus attenuations that may contribute to their altered rate of disease progression. Proviral DNA from strains 99ZATM10 and 01ZATM45 was isolated from peripheral blood mononuclear cells (PBMC) coculture.Virtually full-length genomes and long terminal repeat (LTR) regions were polymerase chain reaction (PCR) amplified, sequenced, and assembled to generate the complete genomes. Phylogenetic analysis confirmed that both isolates were subtype C throughout their genome. Predicted amino acid sequence analysis for all the HIV-1 proteins showed that both viruses had open reading frames for all genes, and encoded proteins of the expected length, except for the rev gene. The 3' end of rev exon 2 did not have the 16-amino acid (aa) truncation characteristic of subtype C viruses, and in addition, had a three-aa extension (GlyCysCys). Rev is a necessary regulatory factor for HIV expression, and changes in the protein may affect viral replication. These results suggest that slower HIV disease progression in these children may be attributed, at least in part, to an altered Rev protein.

Comparison of the effects of high dose testosterone and 19-nortestosterone to a replacement dose of testosterone on strength and body composition in normal men.

We examined the extent to which supraphysiological doses of androgen can modify body composition and strength in normally virilized men. In doubly blind tests, 30 healthy young men received testosterone enanthate (TE) or 19-nortestosterone decanoate (ND), at 100 mg/wk or 300 mg/wk for 6 weeks. The TE-100 mg/wk group served as replacement dose comparison, maintaining pretreatment serum testosterone levels, while keeping all subjects blinded to treatment, particularly through reduction in testicular volumes. Isokinetic strength measurements were made for the biceps brachii and quadriceps femoris muscle groups before treatment and 2-3 days after the 6th injection. Small improvements were noted in all groups but the changes were highly variable; a trend to greater and more consistent strength gain occurred in the TE-300 mg/wk group. There was no change in weight for TE-100 mg/wk but an average gain of 3 kg in each of the other groups. No changes in 4 skinfold thicknesses or in estimated percent body fat were observed. Of 15 circumferences, significant increases were observed only for men receiving TE-300 mg/wk (shoulders) and ND-300 mg/wk (shoulders and chest). The data suggest that high dose androgens increase body mass and may increase strength in normal men but, except for a consistent weight gain with greater than replacement doses, the detectable changes were highly variable and relatively small, especially in comparison to the significant alterations which were observed for other markers of androgen action.

Treatment with propylthiouracil before radioactive iodine therapy is associated with a higher treatment failure rate than therapy with radioactive iodine alone in Graves' disease.

Older reports have suggested that the use of antithyroid drugs with radioactive iodine-131 (RAI) results in higher rates of persistent hyperthyroidism than treatment with RAI alone. Our objective was to determine if propylthiouracil (PTU) given prior to RAI would be associated with a higher single dose RAI failure rate than treatment with RAI alone. Patients were considered treatment failures if a second dose of RAI was required to produce euthyroidism or hypothyroidism. All study patients stopped PTU at least 4 days before RAI therapy and did not receive PTU after RAI. The overall failure rate of one course of treatment in the 86 study patients was 17% (15/86). Persistent hyperthyroidism was seen in 4% of patients (2/48) treated with only RAI and in 34% of patients (13/38) receiving RAI after pretreatment with PTU (p = 0.003). Patients were treated with PTU for a mean of 151 +/- 32 days. There were no significant differences in race, gender, thyroid size, RAI dose, or days of follow-up between patients receiving RAI alone and those receiving PTU before RAI therapy. These data suggest that pretreatment with PTU leads to a higher failure rate even if PTU is discontinued at least 4 days before RAI therapy and not restarted after RAI dosing. Consideration should be given to increasing the dose of RAI in patients pretreated with PTU to ensure adequate treatment of Graves' disease.

The effects of spinal flexion and extension exercises and their associated postures in patients with acute low back pain.

STUDY DESIGN: A prospective randomized clinical trial compared the effects of flexion and extension back exercises and postures among soldiers with acute low back pain. OBJECTIVE: To compare the immediate effects of back exercise on functional status, spinal mobility, straight leg raising, pain severity, and treatment satisfaction, and to determine whether spinal exercise during the acute stage of low back pain reduces recurrent episodes of low back pain. SUMMARY OF BACKGROUND DATA: Conflicting reports exist concerning the efficacy of spinal flexion and extension exercises in patients with low back pain of varying duration. Poor study design and lack of functional outcomes characterize many of these studies. METHODS: One-hundred-forty-nine subjects with acute low back pain received flexion exercise and posture (n = 57), extension exercise and posture (n = 62), or no exercise or posture (n = 30) for 8 weeks. Outcomes were assessed 1, 2, 4 and 8 weeks after treatment onset. A questionnaire assessed the recurrence of low back pain 6-12 months after study entry. RESULTS: Flexion and extension exercise groups did not differ in any outcome over 8 weeks. After 1 week, both exercise groups had reduced disability scores, a higher proportion returning to work, and fewer subjects with a positive straight-leg raise compared with the control group. There was no difference among groups regarding recurrence of low back pain after 6-12 months. CONCLUSIONS: There was no difference for any outcomes between the flexion or extension exercise groups. However, either exercise was slightly more effective than no exercise when patients with acute low back pain were treated.

Impact of prenatal care with reduced frequency of visits in a residency teaching program.

OBJECTIVE: To determine if decreasing the number of prenatal visits for routine obstetric patients affects pregnancy outcome. STUDY DESIGN: A historical control study was designed to include 734 deliveries from January 1 to December 31, 1991, in women who had prenatal care per American College of Obstetricians and Gynecologists Committee Opinion no. 79, January 1990, guidelines for uncomplicated obstetric care. A prospective study cohort of women with 711 deliveries from January 1 to December 31, 1994, underwent prenatal care with modified guidelines to include: first visit at 6-12 weeks to confirm dating and obtain initial laboratory data, second visit at 16-20 weeks to obtain maternal serum alpha-fetoprotein screening, third visit at 24-28 weeks for 28-week laboratory data, fourth visit at 32 weeks, fifth visit at 36 weeks, sixth visit at 38 weeks, seventh visit at 40 weeks and weekly thereafter. Pregnancy outcomes included estimated fetal weight, gestational age at delivery, preeclampsia, Apgar score at one and five minutes and delivery mode. Neonatal outcomes, including stillbirth rate, preterm delivery rate, intraventricular hemorrhage rate, bronchopulmonary dysplasia and neonatal mortality, were evaluated. RESULTS: There were no statistically significant differences in perinatal or neonatal outcomes with decreased prenatal visits from an average of 12 per pregnancy to 8. CONCLUSION: Prenatal visits can be decreased in a teaching hospital in women with uncomplicated pregnancies from the standard number, 12-14 visits, to an average of 7 or 8 per patient without adverse perinatal outcomes.

Detection of human papillomavirus in cervical biopsies of summer camp ROTC cadets with abnormal papanicolaou smears.

STUDY OBJECTIVE: Human papillomavirus (HPV) infections may be the most common sexually transmitted disease (STD) among adolescents and young adults. A strong association exists for certain "high-risk" HPV-type cervical infections and subsequent evolution of cervical cancer and its precursor lesions. The objective of this study was to detect HPV in cervical biopsies of reserve officer training corps (ROTC) cadets attending a regional summer camp who had abnormal screening Papanicolaou (Pap) smears and to better define the spectrum of HPV oncogenic risk types for this population. It was hypothesized that HPV would be detected in the majority of cervical biopsies in keeping with the evolving concept of cervical cancer and its precursors as an STD and the central role of HPV in its development. DESIGN: On arrival for summer military camp training, college women cadets underwent physical examinations that included pelvic examinations for Pap smears. Study participants completed confidential questionnaires after informed consent was obtained. Subjects, who had abnormal Pap smears as defined by reports of atypical squamous cells of undetermined significance (ASCUS) or low- or high-grade squamous intra-epithelial lesions (LGSIL or HGSIL), underwent colposcopic evaluations with cervical biopsies. Subsequently, biopsies were processed for detection of HPV-specific DNA by gel electrophoresis, chemiluminescent oligonucleotide probing, and DNA-RNA hybridization methods after polymerase chain reaction (PCR) amplification. PARTICIPANTS: All female summer camp enrollees presented to the Madigan Army Medical Center Gynecology Clinic for complete physicals before the onset of the training program and were solicited for study inclusion. MAIN OUTCOME MEASURES: All colposcopic biopsy specimens were evaluated for the presence of HPV DNA and subtyped if positive. RESULTS: Representing 42 states, 95% (332) of eligible subjects participated. Mean age was 21.9 years. Racial composition included 70% white, 16% black, 4% Hispanic, 4% Asian, and 6% "other." Eighty-five percent had a history of hetero-sexual activity, with 17.7 years as the mean age at onset. Of the subjects, 12.6% reported a previous diagnosis of a sexually transmitted disease, and 7.8% (26 of 332) had abnormal Pap smears. Of these, colposcopic biopsy results were available for 25 of the 26 abnormal Pap smears. Ninety-six percent (24 of 25) of the colpobiopsies had detectable HPV. Eighty-eight percent (22 of 25) of the subjects with abnormal Pap smears had concurrent abnormal biopsy results. All of these had detectable HPV, confirmed by three different methods, and 29% had dual HPV infection. Sixty percent had "intermediate" or "high-risk" types identified by specific genotyping, 8% had "low-risk" types, and 28% had nontypable HPV. CONCLUSIONS: The data confirm that abnormal Pap smears in this young adult college population are almost always associated with HPV infection, a significant proportion of it being other than low-risk types. The prognostic significance of type-specific cervical HPV infection still needs to be better defined in relation to potential cofactors and host immune response. However, clinicians who provide primary gynecologic care to adolescents and young adults should be aware of the high correlation between abnormal Pap smears and HPV cervical infection and should follow up the patient with the potential risk in mind.

Medical reference databases used by Army primary care physicians in field environments.

A cross-sectional survey of U.S. Army primary care physicians was done to answer two questions: (1) which medical reference materials are Army primary care physicians currently using when deployed to a field environment? and (2) what would they like to have for medical reference in a field environment? Of 740 surveys delivered to their intended recipients, 445 (60%) were returned. Currently, 96% of primary care physicians use books, 37% use journals, and 11% use computer software in their medical reference database. Of those now using books, 72% were satisfied with them, compared with 61% of those using journals and 45% of those using software. The most common book used was the Merck Manual. The most important characteristics desired in a field medical database were broad coverage, ease of use, and light weight. The majority of respondents believe that a good medial reference database is important but that current medical databases limit the quality of the medicine they practice in the field.

Factors associated with stress fracture in young army women: indications for further research.

Several factors which affect bone density and predict risk of osteoporosis (e.g., ethnic origin, amenorrhea) are reportedly associated with a higher incidence of stress fracture in active premenopausal women. The authors surveyed 2,312 active duty Army women for the prevalence of ever having been diagnosed ("told by a doctor") with a stress fracture (16.1% of respondents) and examined the relationship between surveyable risk factors for low bone density and this self-reported stress fracture history (self-reported SF). Current smoking, previous history of amenorrhea (menses absent greater than 6 months), and known family history of osteoporosis were significantly associated with self-reported SF, while black ethnic origin was a protective factor. These data suggest hypotheses of stress fracture pathogenesis in Army women which bear further testing.

Focused obstetrical clinic for active duty junior enlisted service women: model for improved outcomes.

OBJECTIVE: To evaluate the utility of an interdisciplinary clinic in improving perinatal outcomes for all pregnant patients of junior enlisted rank (E4 and below) in response to previous reports that this group is at higher risk for adverse outcomes. METHODS: The study population included all junior enlisted active duty patients (E4 and below) delivering between January 1, 1993, and June 30, 1996. Outcomes for patients receiving care in a focused active duty obstetrical clinic were compared with outcomes in similar cohorts of senior active duty patients (E5 and above) and non-active duty pregnant patients. Evaluation was based on perinatal outcomes, including chorioamnionitis, postpartum hemorrhage, intrauterine growth retardation, cesarean delivery, preterm delivery rates (< 37 weeks), postterm delivery rates (> 41 weeks), postpartum days, mean gestational age at delivery, mean delivery weights, Apgar scores at 1 and 5 minutes, preeclampsia, and premature labor. Variables with potential to confound perinatal outcomes were also studied. Confounding variables included tobacco use, gestational diabetes, chronic hypertension, thyroid disease, history of substance abuse, and alcohol use. Power analysis accomplished before initiation of the study showed adequate sample size (> 240 patients in each group) to demonstrate statistically different rates of preterm delivery. Statistical analysis was done using the chi 2 test for categorical variables and Student's t test for continuous variables. RESULTS: There were no statistical differences between junior active duty patients, senior active duty patients, and non-active duty patients in preterm delivery and other outcome variables. CONCLUSION: The focused obstetrical clinic, conducted for junior enlisted soldiers by a senior nurse practitioner, appears to provide an intervention that ensures perinatal outcomes equal to those of both the non-active duty and the senior active duty population.

Validation of the Madigan ESS simulator.

The Madigan Endoscopic Sinus Surgery (ESS) Simulator, developed by a multi-institution team led by Lockheed Martin, includes force-feedback instrument and virtual endoscope interaction with three-dimensional paranasal anatomy models derived from the Visible Human dataset, supplemented by a variety of graphical and auditory instructional aids embedded in the model. Our formal evaluation of Version 1.2 of the system focused on its validity as an ESS simulator. Run-time and survey data were collected for three groups of subjects on a common protocol progressing through the three basic ESS subtasks: navigation, injection, and dissection. Non-MD subjects performed the tasks on a simplified abstract virtual model with instructional aids (hoops for the navigation path, injection targets, dissection spheres, auditory feedback about task completion, and simulated patient heart rhythm). Non-ENT MDs progressed from this "novice" model to a simulated anterior ethmoidectomy on an "intermediate" model with the aids embedded in the reconstructed and segmented paranasal anatomy. Otolaryngologists ranging from second-year ENT residents through senior staff progressed through both the abstract and intermediate models, and then performed the simulated surgical procedure on an "advanced" model, consisting of the anatomy with no instructional aids. The procedural validity of the simulator is supported by a strong correlation between performance on the simulator and degree of prior ESS experience, by convergent correlation among independent measures of subject task performance, and by subjective evaluations by experienced ESS surgeons.

Adolescent risk behavior and the influence of parents and education.

BACKGROUND: Adolescent involvement with alcohol, drugs, tobacco, sexual relationships, and gang violence begins at increasingly younger ages. Awareness of the dangers and consequences of risk-taking behavior has not had a profound or lasting impact on adolescent behavior, and there appears to be no relation between risk behavior and general knowledge concerning these topics. METHODS: Using paired anonymous questionnaires, we surveyed 215 seventh-grade students and their parents about their experience with and attitudes toward adolescent risk-taking behaviors. The results of each student questionnaire were compared with results of his or her own parents. The survey instrument contained questions concerning tobacco, alcohol, and drug use, sexual activity, gang membership, general knowledge concerning these topics, and parental guidance given. Data were analyzed using the chi2 test of significance. RESULTS: Parent and student recollection of issues discussed and guidance given differed widely, as did the students' understanding of their parents' guidance. Factors found to have a meaningful impact on the reduction of risk behavior in the adolescent population were (1) students perceiving a satisfactory relationship with their parents, and (2) parents successfully communicating their expectations regarding these behaviors to their children. CONCLUSIONS: Parental direction has a powerful effect on the reduction of risk behavior in young adolescents. A limited ability for abstract reasoning during early adolescence requires clear anticipatory guidance by parents and an active effort to maintain communication in the child-parent relationship.

The effect of propylthiouracil on subsequent radioactive iodine therapy in Graves' disease.

OBJECTIVE: Antithyroidal drugs (ATD) are used in the management of Graves' disease either as primary therapy for several months while awaiting remission of the disease or as pretreatment for several weeks prior to definitive radioactive iodine therapy (RAI). We have reported previously that pretreatment with propylthiouracil (PTU) before definitive RAI therapy is associated with a higher RAI treatment failure rate than RAI therapy alone. The objectives of the current study were 2-fold. First, to verify the results of our prior study regarding the effect of PTU used as pretreatment before RAI in a cohort of patients from a different institution and, secondly, to better define the relationship between the number of days off PTU before RAI therapy and therapeutic efficacy of RAI dosing. DESIGN: A retrospective review of Graves' disease patients treated from 1980 to 1994. PATIENTS: Study patients had to meet the following inclusion criteria: radionuclide studies and thyroid hormone values consistent with Graves' disease, at least 1 year of follow-up data available and discontinuation of the ATD at least 4 days before RAI administration. Exclusion criteria included therapy with any ATD other than PTU or ATD therapy during or following RAI dosing. MEASUREMENTS: Effectiveness of RAI therapy, days on PTU, days off PTU and calculated RAI dose to the thyroid were recorded for each subject. We compared the efficacy of RAI therapy in patients treated with PTU (used either as pretreatment in preparation for RAI therapy or as primary long-term therapy) before RAI administrations to those treated with RAI alone with special attention to the number of days on and off PTU before RAI dosing. Patients were considered RAI treatment failures if a second dose of RAI was required to achieve a euthyroid or hypothyroid state. RESULTS: One hundred and sixteen patients met our study criteria. Forty patients received PTU therapy for a mean of 221 +/- 59 days. The PTU was discontinued for a mean of 60 +/- 25 days before RAI dosing. Persistent hyperthyroidism was seen in 9% (7/76) of patients treated with RAI alone. The failure rate of a single dose of radioactive iodine was significantly increased when PTU was discontinued between 4 and 7 days before the administration of RAI (29% vs 9% for RAI alone, P = 0.039). PTU discontinued for at least 1 week before RAI dosing was associated with a nearly 2-fold increase in failure rate, but this difference did not achieve significance (17% vs 9% for RAI alone, P = 0.24). Examining only those patients receiving PTU, patients who had successful single dose RAI therapy tended to receive a higher dose of RAI than patients failing RAI therapy (480 +/- 30 vs 410 +/- 40 MBq administered dose, P = 0.18; and 8.0 +/- 0.9 vs 5.5 +/- 1.1 MBq/g thyroid tissue calculated dose, P = 0.21). Furthermore, total serum thyroxine at diagnosis was significantly higher in patients failing RAI therapy after PTU administration than in patients successfully treated with RAI after receiving PTU (316 +/- 40 vs 225 +/- 13 nmol/L, P = 0.03). CONCLUSIONS: Propylthiouracil discontinued 4-7 days before radioiodine dosing is associated with a significant increase in the failure rate of a single dose of radioiodine. Discontinuation of the propylthiouracil for at least a week before radioiodine administration is associated with a higher, although not statistically significant, radioiodine failure rate. In patients that require treatment with propylthiouracil before radioiodine therapy, a higher total serum thyroxine level at diagnosis is associated with an increased rate of radioiodine failure. Consideration should be given to increasing empirically the dose of radioiodine administered to Graves' disease patients that have received propylthiouracil within a week of radioiodine administration in an effort to decrease the radioiodine failure rate to an acceptable level.

Effect of eye color on heart rate response to intramuscular administration of atropine.

Melanin has been previously shown to modify the mydriatic response to atropine instillation. Skin and iris pigmentation has also been shown to modify aspects of the heart rate response to injected atropine, although these observations have been generally overlooked. In this study, 20 healthy non-smoker male subjects, ages 20-30 years, were injected by two different automatic injector devices and the mydriatic and heart rate responses in the first 90 min were reported. The group included 8 brown-eyed, 4 hazel-eyed, and 8 blue-eyed subjects. Although there were differences in the rate of atropine delivery between the two injection devices, the heart rate responses were independently modified by eye color to a magnitude of difference as great as the differences between injectors. Subjects with more pigmented irides (brown-eyed) showed a more rapid rise in heart rate compared to less pigmented irides (hazel-eyed and blue-eyed subjects). Following injection by the device with a slower atropine absorption rate, these differences were particularly enhanced and an abbreviated bradycardic phase of the heart rate response was observed for the brown-eyed subjects. This observation confirms earlier reports and suggests the possibility of an interference by melanin (in the iris or elsewhere) in atropine accessibility to selected muscarinic target sites.

The natural history of pelvic organ support in pregnancy.

Little is known about the anatomic and physiologic changes in the pelvic floor that occur during pregnancy. The purpose of this study was to prospectively document pelvic organ support throughout pregnancy using the standardized system of the International Continence Society, also known as the Pelvic Organ Prolapse Quantification (POPQ) Staging System. Pelvic organ support evaluations were performed in nulliparous pregnant women presenting for routine obstetric care during each trimester. POPQ stage assignments and POPQ component measurements were compared for first-, second- and third-trimester examinations. Overall POPQ stage was significantly higher in the third trimester than in the first (P=0.001). Individual POPQ points which showed significant differences between the first and third trimesters include Aa, PB, Ap, Ba, Bp, TVL and GH. These findings probably represent normal physiologic changes of the pelvic floor during pregnancy, but suggest that significant changes may be objectively demonstrated prior to delivery.

Use of a focussed teen prenatal clinic at a military teaching hospital: model for improved outcomes of unmarried mothers.

We evaluated the utility of a focussed, multidisciplinary adolescent clinic in improving perinatal outcomes. The study population included all delivering unmarried teenagers (13-19 years) from January 1, 1993 to December 31, 1995 attending the focussed adolescent obstetrical clinic compared to a similar cohort of married teenagers (13-19 years), married 20-24 year-old patients, and unmarried 20-24 year-old patients. There were no statistical differences in chorioamnionitis, intrauterine growth retardation (IUGR), postpartum haemorrhage, maternal weight gain, mean gestational age at delivery, preterm delivery rates (<37 weeks), low birth-weight (<2,500 g), Caesarean delivery, postterm delivery rates (>41 weeks), macrosomia (>4,000 g), placental abruption, chronic hypertension, alcohol use, Apgar scores or stillbirth rates or neonatal death rates among the 4 groups studied. Statistical differences were noted in mean delivery weights (p<0.05), preeclampsia (p<0.004), gestational diabetes (p<0.01), history of substance abuse (p<0.0001), tobacco use (p<0.0001), and forceps delivery rates (p<0.004). However, in the teen cohort none of these differences appeared to adversely affect perinatal outcomes in our patients. The focussed, adolescent obstetrical clinic appears to provide perinatal morbidities equal to a low-risk, general population generating better than expected outcomes for pregnant teenagers.

Frequency of -163 C>A and 63 C>G single nucleotide polymorphism of cytochrome P450 1A2 in two African populations.

Cytochrome P450 1A2 (CYP1A2) is an important member of the cytochrome P450 superfamily of enzymes because of its involvement in the metabolism of some carcinogens and therapeutically important drugs. As a result, factors affecting the activity of the enzyme are the focus of considerable research effort as they may have important pharmacological or toxicological implications. CYP1A2 has been shown to exhibit a genetic polymorphism with most of the data, however, coming from studies in Caucasian and Oriental populations. In this study therefore, we investigated the frequencies of two point mutations, -163C>A and 63C>G, in two Bantu African populations. A total of 214 healthy subjects were recruited from Zimbabwe (n=143) and Tanzania (n=71). The two single nucleotide polymorphisms were detected using polymerase chain reaction-restriction fragment length polymorphism analysis. The frequency of -163A was 57% (95% confidence interval (CI), 54%, 60%) and 49% (95% CI, 45%, 53%) among Zimbabweans and Tanzanians, respectively, but the difference between the two populations was not statistically significant (p=0.123). The base change 63 C>G was not found in any of the subjects from the two populations. We report here a high frequency of -163 C>A base change and an absence of the 63 C>G change in the two African populations.

Atypical hyperplasia in the era of stereotactic core needle biopsy.

BACKGROUND AND OBJECTIVES: To characterize both atypical hyperplasia (AH) and the malignancies typically present at open surgical biopsy in women diagnosed with AH by stereotactic core needle biopsy (SCNB). METHODS: Patients with AH diagnosed by SCNB were advised to undergo surgical biopsy to rule out an associated malignancy. Mammography findings, pathology reports and follow-up data were analyzed. RESULTS: AH was identified by SCNB in 38 of 893 (4.3%) patients. Carcinoma was identified in 12 of 33 (36.4%) patients who went on to surgical biopsy. Ductal carcinoma in situ (DCIS) was present in 11 of the 12 patients with malignancy. There were no characteristic mammographic findings which would identify patients with carcinoma. CONCLUSIONS: When SCNB returns a diagnosis of AH there is a substantial risk of an associated malignancy in the breast. There appear to be no definitive criteria to distinguish which patients harbor a malignancy, and surgical biopsy should always serve as an adjunct diagnostic procedure.