Women's Hospital

BACKGROUND: Very preterm infants are at high risk for adverse neurodevelopmental outcomes. Magnetic resonance imaging (MRI) has been proposed as a means of predicting neurodevelopmental outcomes in this population. METHODS: We studied 167 very preterm infants (gestational age at birth, 30 weeks or less) to assess the associations between qualitatively defined white-matter and gray-matter abnormalities on MRI at term equivalent (gestational age of 40 weeks) and the risks of severe cognitive delay, severe psychomotor delay, cerebral palsy, and neurosensory (hearing or visual) impairment at 2 years of age (corrected for prematurity). RESULTS: At two years of age, 17 percent of infants had severe cognitive delay, 10 percent had severe psychomotor delay, 10 percent had cerebral palsy, and 11 percent had neurosensory impairment. Moderate-to-severe cerebral white-matter abnormalities present in 21 percent of infants at term equivalent were predictive of the following adverse outcomes at two years of age: cognitive delay (odds ratio, 3.6; 95 percent confidence interval, 1.5 to 8.7), motor delay (odds ratio, 10.3; 95 percent confidence interval, 3.5 to 30.8), cerebral palsy (odds ratio, 9.6; 95 percent confidence interval, 3.2 to 28.3), and neurosensory impairment (odds ratio, 4.2; 95 percent confidence interval, 1.6 to 11.3). Gray-matter abnormalities (present in 49 percent of infants) were also associated, but less strongly, with cognitive delay, motor delay, and cerebral palsy. Moderate-to-severe white-matter abnormalities on MRI were significant predictors of severe motor delay and cerebral palsy after adjustment for other measures during the neonatal period, including findings on cranial ultrasonography. CONCLUSIONS: Abnormal findings on MRI at term equivalent in very preterm infants strongly predict adverse neurodevelopmental outcomes at two years of age. These findings suggest a role for MRI at term equivalent in risk stratification for these infants.

BACKGROUND: The role of adjuvant chemotherapy in stage II colon cancer continues to be debated. The presence of circulating tumor DNA (ctDNA) after surgery predicts very poor recurrence-free survival, whereas its absence predicts a low risk of recurrence. The benefit of adjuvant chemotherapy for ctDNA-positive patients is not well understood. METHODS: We conducted a trial to assess whether a ctDNA-guided approach could reduce the use of adjuvant chemotherapy without compromising recurrence risk. Patients with stage II colon cancer were randomly assigned in a 2:1 ratio to have treatment decisions guided by either ctDNA results or standard clinicopathological features. For ctDNA-guided management, a ctDNA-positive result at 4 or 7 weeks after surgery prompted oxaliplatin-based or fluoropyrimidine chemotherapy. Patients who were ctDNA-negative were not treated. The primary efficacy end point was recurrence-free survival at 2 years. A key secondary end point was adjuvant chemotherapy use. RESULTS: Of the 455 patients who underwent randomization, 302 were assigned to ctDNA-guided management and 153 to standard management. The median follow-up was 37 months. A lower percentage of patients in the ctDNA-guided group than in the standard-management group received adjuvant chemotherapy (15% vs. 28%; relative risk, 1.82; 95% confidence interval [CI], 1.25 to 2.65). In the evaluation of 2-year recurrence-free survival, ctDNA-guided management was noninferior to standard management (93.5% and 92.4%, respectively; absolute difference, 1.1 percentage points; 95% CI, -4.1 to 6.2 [noninferiority margin, -8.5 percentage points]). Three-year recurrence-free survival was 86.4% among ctDNA-positive patients who received adjuvant chemotherapy and 92.5% among ctDNA-negative patients who did not. CONCLUSIONS: A ctDNA-guided approach to the treatment of stage II colon cancer reduced adjuvant chemotherapy use without compromising recurrence-free survival. (Supported by the Australian National Health and Medical Research Council and others; DYNAMIC Australian New Zealand Clinical Trials Registry number, ACTRN12615000381583.).

The production and deployment of phagocytes are central functions of the hematopoietic system. In the 1950s, radioisotopic studies demonstrated the high production rate and short lifespan of neutrophils and allowed researchers to follow the monocytes as they moved from the marrow through the blood to become tissue macrophages, histiocytes, and dendritic cells. Subsequently, the discovery of the colony-stimulating factors greatly improved understanding the regulation of phagocyte production. The discovery of the microbicidal myeloperoxidase-H2O2-halide system and the importance of NADPH oxidase to the generation of H2O2 also stimulated intense interest in phagocyte disorders. More recent research has focused on membrane receptors and the dynamics of the responses of phagocytes to external factors including immunoglobulins, complement proteins, cytokines, chemokines, integrins, and selectins. Phagocytes express toll-like receptors that aid in the clearance of a wide range of microbial pathogens and their products. Phagocytes are also important sources of pro- and anti-inflammatory cytokines, thus participating in host defenses through a variety of mechanisms. Over the last 50 years, many genetic and molecular disorders of phagocytes have been identified, leading to improved diagnosis and treatment of conditions which predispose patients to the risk of recurrent fevers and infectious diseases.

BACKGROUND: Minimally invasive surgery was adopted as an alternative to laparotomy (open surgery) for radical hysterectomy in patients with early-stage cervical cancer before high-quality evidence regarding its effect on survival was available. We sought to determine the effect of minimally invasive surgery on all-cause mortality among women undergoing radical hysterectomy for cervical cancer. METHODS: We performed a cohort study involving women who underwent radical hysterectomy for stage IA2 or IB1 cervical cancer during the 2010-2013 period at Commission on Cancer-accredited hospitals in the United States. The study used inverse probability of treatment propensity-score weighting. We also conducted an interrupted time-series analysis involving women who underwent radical hysterectomy for cervical cancer during the 2000-2010 period, using the Surveillance, Epidemiology, and End Results program database. RESULTS: In the primary analysis, 1225 of 2461 women (49.8%) underwent minimally invasive surgery. Women treated with minimally invasive surgery were more often white, privately insured, and from ZIP Codes with higher socioeconomic status, had smaller, lower-grade tumors, and were more likely to have received a diagnosis later in the study period than women who underwent open surgery. Over a median follow-up of 45 months, the 4-year mortality was 9.1% among women who underwent minimally invasive surgery and 5.3% among those who underwent open surgery (hazard ratio, 1.65; 95% confidence interval [CI], 1.22 to 2.22; P=0.002 by the log-rank test). Before the adoption of minimally invasive radical hysterectomy (i.e., in the 2000-2006 period), the 4-year relative survival rate among women who underwent radical hysterectomy for cervical cancer remained stable (annual percentage change, 0.3%; 95% CI, -0.1 to 0.6). The adoption of minimally invasive surgery coincided with a decline in the 4-year relative survival rate of 0.8% (95% CI, 0.3 to 1.4) per year after 2006 (P=0.01 for change of trend). CONCLUSIONS: In an epidemiologic study, minimally invasive radical hysterectomy was associated with shorter overall survival than open surgery among women with stage IA2 or IB1 cervical carcinoma. (Funded by the National Cancer Institute and others.).

To determine whether insulin resistance occurs in polycystic ovarian disease (PCO) in the absence of obesity and acanthosis nigricans, circulating levels of insulin in response to oral glucose administration were measured in 10 nonobese PCO patients without acanthosis nigricans and in 10 normal women matched for weight and height. Mean serum testosterone (T), androstenedione (A), dehydroepiandrosterone (D), D sulfate, and LH levels were significantly elevated in the PCO patients compared to those in control subjects. In PCO patients, the mean +/- SE basal insulin level (18.7 +/- 2.9 microU/ml) and the sum of the insulin levels in response to glucose (674 +/- 119 microU/ml) were significantly greater than those in the control group (11.0 +/- 0.8 microU/ml and 248 +/- 29 microU/ml, respectively). In all subjects, serum levels of T and A, but not D and D sulfate, were significantly correlated to basal insulin levels and insulin sums. Serum cortisol, GH, and PRL levels were similar in both groups. These results indicate that in PCO, a significant degree of insulin resistance exists, which clearly is not related to obesity. The positive correlation of serum T and A levels to circulating insulin levels in this study suggests that the insulin resistance in PCO may be, in part, a consequence of hyperandrogenism.

BACKGROUND: Reduced methylation of DNA may contribute to loss of the normal controls on proto-oncogene expression. In humans, hypomethylation of DNA has been observed in colorectal cancers and in their adenomatous polyp precursors. Accumulation of DNA methylation abnormalities, observed during progression of human colorectal neoplasia, may be influenced by certain dietary factors. The apparent protective effect of fresh fruits and vegetables, the major folate sources, on colorectal cancer incidence suggests that a methyl-deficient diet contributes to occurrence of this malignancy. Low dietary folate and methionine and high intake of alcohol may reduce levels of S-adenosylmethionine, which is required for DNA methylation. PURPOSE: To determine if dietary factors that may influence methyl availability are related to colorectal adenomas, we prospectively examined the association of folate, methionine, and alcohol intakes and risk of colorectal adenoma. METHODS: We assessed dietary intake for a 1-year period for women of the Nurses' Health Study, started in 1976, and for men of the Health Professionals Follow-up Study, started in 1986--using a semiquantitative food frequency questionnaire. Adenomatous polyps of the left colon or rectum were diagnosed in 564 of 15,984 women who had had an endoscopy between 1980 and 1990 and in 331 of 9490 men who had undergone an endoscopy between 1986 and 1990. RESULTS: High dietary folate was inversely associated with risk of colorectal adenoma in women (multivariate relative risk [RR] = 0.66; 95% confidence interval [CI] = 0.46-0.95 between high and low quintiles of intake) and in men (RR = 0.63; 95% CI = 0.41-0.98) after adjusting for age, family history, indications for endoscopy, history of previous endoscopy, total energy intake, saturated fat intake, dietary fiber, and body mass index. Relative to nondrinkers, drinkers of more than 30 g of alcohol daily (about two drinks) had an elevated risk of adenoma (in women, RR = 1.84, 95% CI = 1.19-2.86; in men, RR = 1.64, 95% CI = 0.92-2.93). Methionine intake was inversely associated with risk of adenomas 1 cm or larger (RR = 0.62; 95% CI = 0.46-0.85, combining men and women). CONCLUSIONS: Folate, alcohol, and methionine could influence methyl group availability, and a methyl-deficient diet may be linked to early stages of colorectal neoplasia. A dietary pattern that increases methyl availability could reduce incidence of colorectal cancer. IMPLICATIONS: These data support efforts to increase dietary folate in segments of the population having diets with low intakes of this nutrient.

BACKGROUND: The three approaches to hysterectomy for benign disease are abdominal hysterectomy (AH), vaginal hysterectomy (VH), and laparoscopic hysterectomy (LH). Laparoscopic hysterectomy has three further subdivisions depending on the part of the procedure performed laparoscopically. OBJECTIVES: To assess the most beneficial and least harmful surgical approach to hysterectomy for women with benign gynaecological conditions. SEARCH STRATEGY: We searched the Cochrane Menstrual Disorders and Subfertility Group Specialised Register of controlled trials (15 August 2008), CENTRAL (The Cochrane Library 2008, Issue 3), MEDLINE (1950 to August 2008), EMBASE (1980 to August 2008), Biological Abstracts (1969 to August 2008), the National Research Register, and relevant citation lists. SELECTION CRITERIA: Only randomised controlled trials comparing one surgical approach to hysterectomy with another were included. DATA COLLECTION AND ANALYSIS: Independent selection of trials and data extraction were employed following Cochrane guidelines. MAIN RESULTS: There were 34 included studies with 4495 women. The benefits of VH versus AH were speedier return to normal activities (mean difference (MD) 9.5 days), fewer febrile episodes or unspecified infections (odds ratio (OR) 0.42), and shorter duration of hospital stay (MD 1.1 days). The benefits of LH versus AH were speedier return to normal activities (MD 13.6 days), lower intraoperative blood loss (MD 45 cc), a smaller drop in haemoglobin (MD 0.55 g/dl), shorter hospital stay (MD 2.0 days), and fewer wound or abdominal wall infections (OR 0.31) at the cost of more urinary tract (bladder or ureter) injuries (OR 2.41) and longer operation time (MD 20.3 minutes). The benefits of LAVH versus TLH were fewer febrile episodes or unspecified infection (OR 3.77) and shorter operation time (MD 25.3 minutes). There was no evidence of benefits of LH versus VH and the operation time (MD 39.3 minutes) as well as substantial bleeding (OR 2.76) were increased in LH. For some important outcomes, the analyses were underpowered to detect important differences or they were simply not reported in trials. Data were absent for many important long-term outcome measures. AUTHORS' CONCLUSIONS: Because of equal or significantly better outcomes on all parameters, VH should be performed in preference to AH where possible. Where VH is not possible, LH may avoid the need for AH however the length of the surgery increases as the extent of the surgery performed laparoscopically increases. The surgical approach to hysterectomy should be decided by the woman in discussion with her surgeon in light of the relative benefits and hazards.

BACKGROUND: Term infants who are small for gestational age appear prone to the development of insulin resistance during childhood. We hypothesized that insulin resistance, a marker of type 2 diabetes mellitus, would be prevalent among children who had been born prematurely, irrespective of whether they were appropriate for gestational age or small for gestational age. METHODS: Seventy-two healthy prepubertal children 4 to 10 years of age were studied: 50 who had been born prematurely (32 weeks' gestation or less), including 38 with a birth weight that was appropriate for gestational age (above the 10th percentile) and 12 with a birth weight that was low (i.e., who were small) for gestational age, and 22 control subjects (at least 37 weeks' gestation, with a birth weight above the 10th percentile). Insulin sensitivity was measured with the use of paired insulin and glucose data obtained by frequent measurements during intravenous glucose-tolerance tests. RESULTS: Children who had been born prematurely, whether their weight was appropriate or low for gestational age, had an isolated reduction in insulin sensitivity as compared with controls (appropriate-for-gestational-age group, 14.2x10(-4) per minute per milliunit per liter [95 percent confidence interval, 11.5 to 16.2]; small-for-gestational-age group, 12.9x10(-4) per minute per milliunit per liter [95 percent confidence interval, 9.7 to 17.4]; and control group, 21.6x10(-4) per minute per milliunit per liter [95 percent confidence interval, 17.1 to 27.4]; P=0.002). There were no significant differences in insulin sensitivity between the two premature groups (P=0.80). As compared with controls, both groups of premature children had a compensatory increase in acute insulin release (appropriate-for-gestational-age group, 2002 pmol per liter [95 percent confidence interval, 1434 to 2432] [corrected]; small-for-gestational-age group, 2253 pmol per liter [95 percent confidence interval, 1622 to 3128]; and control group, 1148 pmol per liter [95 percent confidence interval, 875 to 1500]; P<0.001). CONCLUSIONS: Like children who were born at term but who were small for gestational age, children who were born prematurely have an isolated reduction in insulin sensitivity, which may be a risk factor for type 2 diabetes mellitus.

BACKGROUND: Systematic pelvic and paraaortic lymphadenectomy has been widely used in the surgical treatment of patients with advanced ovarian cancer, although supporting evidence from randomized clinical trials has been limited. METHODS: We intraoperatively randomly assigned patients with newly diagnosed advanced ovarian cancer (International Federation of Gynecology and Obstetrics stage IIB through IV) who had undergone macroscopically complete resection and had normal lymph nodes both before and during surgery to either undergo or not undergo lymphadenectomy. All centers had to qualify with regard to surgical skills before participation in the trial. The primary end point was overall survival. RESULTS: A total of 647 patients underwent randomization from December 2008 through January 2012, were assigned to undergo lymphadenectomy (323 patients) or not undergo lymphadenectomy (324), and were included in the analysis. Among patients who underwent lymphadenectomy, the median number of removed nodes was 57 (35 pelvic and 22 paraaortic nodes). The median overall survival was 69.2 months in the no-lymphadenectomy group and 65.5 months in the lymphadenectomy group (hazard ratio for death in the lymphadenectomy group, 1.06; 95% confidence interval [CI], 0.83 to 1.34; P = 0.65), and median progression-free survival was 25.5 months in both groups (hazard ratio for progression or death in the lymphadenectomy group, 1.11; 95% CI, 0.92 to 1.34; P = 0.29). Serious postoperative complications occurred more frequently in the lymphadenectomy group (e.g., incidence of repeat laparotomy, 12.4% vs. 6.5% [P = 0.01]; mortality within 60 days after surgery, 3.1% vs. 0.9% [P = 0.049]). CONCLUSIONS: Systematic pelvic and paraaortic lymphadenectomy in patients with advanced ovarian cancer who had undergone intraabdominal macroscopically complete resection and had normal lymph nodes both before and during surgery was not associated with longer overall or progression-free survival than no lymphadenectomy and was associated with a higher incidence of postoperative complications. (Funded by Deutsche Forschungsgemeinschaft and the Austrian Science Fund; LION ClinicalTrials.gov number, NCT00712218.).

Hormonal inhibition of adenylate cyclase is mediated by a guanine nucleotide regulatory protein (Ni) which is different from the one which mediates hormonal stimulation. There is substantial evidence that the active component of Ni (termed alpha i can be ADP-ribosylated by a toxin from Bordetella pertussis. We have found that in bovine cerebral cortex there are three proteins of similar molecular weight (39,000-41,000) which are modified by pertussis toxin. We have purified these proteins and have resolved the 41,000-dalton protein from the 40,000/39,000-dalton doublet. All three forms of pertussis toxin substrate can be isolated in free form or together with a 36,000 beta component. We have also purified this beta component. ADP-ribosylation of the three pertussis toxin substrates is greatly enhanced by the addition of the purified beta component. This makes possible an assay of beta subunit activity based on its interaction with alpha i. The three forms of pertussis toxin substrate which we have purified differ in two functions: susceptibility to ADP-ribosylation and GTPase activity. The 41,000-dalton protein is more readily ADP-ribosylated by pertussis toxin than the smaller forms. The 39,000-dalton protein has GTPase activity with a low Km (0.3 microM) for GTP. The GTPase activity can be doubled by phospholipids. The GTPase activity of the 41,000-dalton protein is almost undetectable. It is not yet known what the relationship of the forms is to each other. The smaller forms may be derived from the larger by proteolysis or it may be intrinsically different. It remains to be shown whether one of the forms represents a different type of regulatory protein which transmits a hormonal signal to effectors other than adenylate cyclase.

Quantitative sensory testing (QST) is a psychophysical method used to quantify somatosensory function in response to controlled stimuli in healthy subjects and patients. Although QST shares similarities with the quantitative assessment of hearing or vision, which is extensively used in clinical practice and research, it has not gained a large acceptance among clinicians for many reasons, and in significant part because of the lack of information about standards for performing QST, its potential utility, and interpretation of results. A consensus meeting was convened by the Neuropathic Pain Special Interest Group of the International Association for the Study of Pain (NeuPSIG) to formulate recommendations for conducting QST in clinical practice and research. Research studies have confirmed the utility of QST for the assessment and monitoring of somatosensory deficits, particularly in diabetic and small fiber neuropathies; the assessment of evoked pains (mechanical and thermal allodynia or hyperalgesia); and the diagnosis of sensory neuropathies. Promising applications include the assessment of evoked pains in large-scale clinical trials and the study of conditioned pain modulation. In clinical practice, we recommend the use QST for screening for small and large fiber neuropathies; monitoring of somatosensory deficits; and monitoring of evoked pains, allodynia, and hyperalgesia. QST is not recommended as a stand-alone test for the diagnosis of neuropathic pain. For the conduct of QST in healthy subjects and in patients, we recommend use of predefined standardized stimuli and instructions, validated algorithms of testing, and reference values corrected for anatomical site, age, and gender. Interpretation of results should always take into account the clinical context, and patients with language and cognitive difficulties, anxiety, or litigation should not be considered eligible for QST. When appropriate standards, as discussed here, are applied, QST can provide important and unique information about the functional status of somatosensory system, which would be complementary to already existing clinical methods.

The prevalence of dysmenorrhoea (painful menstrual cramps of uterine origin) is difficult to determine because of different definitions of the condition—prevalence estimates vary from 45% to 95%. However, dysmenorrhoea seems to be the most common gynaecological condition in women regardless of age and nationality.1 2 Absenteeism from work and school as a result of dysmenorrhoea is common (13% to 51% women have been absent at least once and 5% to 14% are often absent owing to the severity of symptoms).3 Dysmenorrhoea, especially when it is severe, is associated with a restriction of activity and absence from school or work. Yet despite this substantial effect on their quality of life and general wellbeing, few women with dysmenorrhoea seek treatment as they believe it would not help.w1 We used Medline (1966 to March 2006) to conduct a literature search of the Cochrane Database of Systematic Reviews on the Cochrane Library, issue 1, 2006, and we searched citation lists of relevant publications, including studies for randomised controlled trials (RCTs) and review articles. We used the following subject headings and keywords: dysmenorrhoea, dysmenorrhea, menstrual pain, period pain, and pelvic pain. Dysmenorrhoea is commonly divided into two categories based on pathophysiology (table). Primary dysmenorrhoea is menstrual pain without organic disease, and secondary dysmenorrhoea is menstrual pain associated with an identifiable disease. Common causes of secondary dysmenorrhoea include endometriosis, fibroids (myomas), adenomyosis, endometrial polyps, pelvic inflammatory disease, and the use of an intrauterine contraceptive device. View this table: Differential diagnosis of primary and secondary dysmenorrhoea Until recently, many medical and gynaecological texts ascribed the source of dysmenorrhoea to emotional or psychological problems—for example, anxiety, emotional instability, a faulty outlook on sex and menstruation, and imitation of the mother's feelings about menstruation.w2 However, experimental and clinical research has identified a physiological reason for dysmenorrhoea—the production of …

Gender is increasingly understood as defining a system of power relations embedded in other power relations. Psychological research on gender-which has most often focused on analysis of sex differences, within-sex variability, and gender roles-has begun to incorporate this new understanding. By drawing on three resources, psychologists can make more rapid progress in understanding gender's significance for psychological processes: social science theories that link the individual and social levels of analysis; constructs (such as identity) that bridge the social and individual levels; and conceptual tools generated in feminist theory, perhaps especially intersectionality. We review these resources, cite active research programs that have employed them, and conclude by offering some practical suggestions about how to incorporate these resources into our research.

PURPOSE: To determine factors contributing to the infrequent provision of spiritual care (SC) by nurses and physicians caring for patients at the end of life (EOL). PATIENTS AND METHODS: This is a survey-based, multisite study conducted from March 2006 through January 2009. All eligible patients with advanced cancer receiving palliative radiation therapy and oncology physician and nurses at four Boston academic centers were approached for study participation; 75 patients (response rate = 73%) and 339 nurses and physicians (response rate = 63%) participated. The survey assessed practical and operational dimensions of SC, including eight SC examples. Outcomes assessed five factors hypothesized to contribute to SC infrequency. RESULTS: Most patients with advanced cancer had never received any form of spiritual care from their oncology nurses or physicians (87% and 94%, respectively; P for difference = .043). Majorities of patients indicated that SC is an important component of cancer care from nurses and physicians (86% and 87%, respectively; P = .1). Most nurses and physicians thought that SC should at least occasionally be provided (87% and 80%, respectively; P = .16). Majorities of patients, nurses, and physicians endorsed the appropriateness of eight examples of SC (averages, 78%, 93%, and 87%, respectively; P = .01). In adjusted analyses, the strongest predictor of SC provision by nurses and physicians was reception of SC training (odds ratio [OR] = 11.20, 95% CI, 1.24 to 101; and OR = 7.22, 95% CI, 1.91 to 27.30, respectively). Most nurses and physicians had not received SC training (88% and 86%, respectively; P = .83). CONCLUSION: Patients, nurses, and physicians view SC as an important, appropriate, and beneficial component of EOL care. SC infrequency may be primarily due to lack of training, suggesting that SC training is critical to meeting national EOL care guidelines.

Background: Laboratory, clinical, and epidemiologic studies have recently suggested that regular use of aspirin can reduce colorectaJ cancer incidence or mortality. However, observational epidemiologic analyses have had limited opportunity to control for confounding bias or to specify aspirin doses used. Purpose: Our purpose was to examine the relationship between regular use of low-dose aspirin and incidence of invasive and noninvasive colorectal tumors by utilizing data from the Physicians‘ Health Study, a randomized, double-blinded, placebo-controlled trial of aspirin and beta carotene. We also attempted to determine whether invasive cancers among aspirin users were associated with rectal bleeding and early stage at diagnosis. Methods : The Physicians’ Health Study includes 22071 U.S. male physicians. The aspirin arm was terminated in 1988 after a mean follow-up of 5 years. Stage at diagnosis and signs and/or symptoms during presentation were abstracted from medical records. Cox proportional hazards models were used to estimate relative risk (RR), 95%confidence intervals (CIs), and the association between aspirin and bleeding. Differences between aspirin and placebo groups in tumor risk over time were visualized with Kaplan-Meier curves. We assessed the association between aspirin and stage at diagnosis with a Mann-Whitney rank sum statistic for non-parametric comparison of two ordinal distributions. Results: The RR of developing colorectal cancer for aspirin compared with placebo was 1.15 (95%CI 0.80–1.65). For in situ cancers and polyps, the RR was 0.86 (95% CI 0.68–1.10). There was no significant trend for decreasing RR by year of follow-up for invasive cancers (P 09) or noninvasive tumors (P .96). Aspirin and placebo groups did not differ in stage or prevalence of rectal bleeding at diagnosis. Conclusions: Regular aspirin use, at a dose adequate for preventing myocardial infarction, was not associated with a substantial reduction in the incidence of colorectal cancer during 5 years of randomized treatment and follow-up. A small decrease in polyps in the aspirin group could not be reliably distinguished from a chance association. Our results suggest that among low-dose aspirin users, (a) colorectal cancer mortality is not likely to be reduced by earlier detection and (b) incidence is not likely to be increased due to aspirin-induced gastrointestinal bleeding. Implications: The potential for a benefit from higher doses of aspirin or longer duration of use should be addressed by more detailed observational epidemiologic studies and prevention trials with longer follow-up of randomized participants. [J Natl Cancer Inst 85: 1220–1224, 1993]

Recent publications have suggested that use of the Pipelle endometrial suction curette is a safe and effective method by which to obtain samples of endometrial tissue. To address this issue, we performed a randomized clinical trial comparing the Pipelle to the Tis-u-trap in 156 patients. The Pipelle was as effective as the Tis-u-trap in obtaining endometrial samples in both the adequacy of the specimen (Pipelle 88%, Tis-u-trap 84%) and the quality of the specimen (P = .26). This trial confirms the favorable observational reports on the use of the Pipelle for endometrial biopsy.

Preterm labor leading to preterm delivery (<37 weeks' gestation) affects approximately 5-7% of live births in developed countries, but significantly higher in developing countries. Prematurity due to preterm birth (PTB) accounts for around 28% of neonatal mortality worldwide. Approximately 45-50% of PTBs are idiopathic or spontaneous, 30% are related to preterm rupture of membranes, and another 15-20% are attributed to medically indicated or elective preterm deliveries. The rate of spontaneous PTB is also increasing and the exact cause is still unclear. Generalized approaches in screening for high risk status of preterm labor and interventions have failed to reduce PTB rates. PTB presents a clinical dilemma due to etiologic, pathophysiologic and genetic heterogeneities. Racial disparity in PTB rates observed in the US further complicates its understanding. PTB is a complex phenotype and is not initiated by a single etiologic agent. Etiologic factors operate through multiple pathophysiologic pathways, and these pathways include highly overlapping biomarkers and molecular factors creating pathophysiologic heterogeneities. In this article, the current understanding of PTB pathophysiology is reviewed and the need for a much broader approach in research, analysis and interpretation of data is explained, where environmental and race/ethnicity specific risk factors may dictate specific pathways leading to PTB. Recent data on amniotic fluid biomarkers and maternal and fetal genetic variants, which indicate huge disparity between races in the US, are also reviewed. These data suggest that gene-gene interactions and gene-environmental interactions produce distinct pathophysiologic pathways with respect to an individual's genetic make-up and environmental risk exposure. Current strategies of high risk screening and intervention measures may not be generalized, and a more individualized approach may be required to understand PTB and its prevention.

Spermatogenesis has been intensely studied in rodents but remains poorly understood in humans. Here, we used single-cell RNA sequencing to analyze human testes. Clustering analysis of neonatal testes reveals several cell subsets, including cell populations with characteristics of primordial germ cells (PGCs) and spermatogonial stem cells (SSCs). In adult testes, we identify four undifferentiated spermatogonia (SPG) clusters, each of which expresses specific marker genes. We identify protein markers for the most primitive SPG state, allowing us to purify this likely SSC-enriched cell subset. We map the timeline of male germ cell development from PGCs through fetal germ cells to differentiating adult SPG stages. We also define somatic cell subsets in both neonatal and adult testes and trace their developmental trajectories. Our data provide a blueprint of the developing human male germline and supporting somatic cells. The PGC-like and SSC markers are candidates to be used for SSC therapy to treat infertility.

We present a new algorithm for the nonrigid registration of three-dimensional magnetic resonance (MR) intraoperative image sequences showing brain shift. The algorithm tracks key surfaces of objects (cortical surface and the lateral ventricles) in the image sequence using a deformable surface matching algorithm. The volumetric deformation field of the objects is then inferred from the displacements at the boundary surfaces using a linear elastic biomechanical finite-element model. Two experiments on synthetic image sequences are presented, as well as an initial experiment on intraoperative MR images showing brain shift. The results of the registration algorithm show a good correlation of the internal brain structures after deformation, and a good capability of measuring surface as well as subsurface shift. We measured distances between landmarks in the deformed initial image and the corresponding landmarks in the target scan. Cortical surface shifts of up to 10 mm and subsurface shifts of up to 6 mm were recovered with an accuracy of 1 mm or less and 3 mm or less respectively.

Maternal stress is commonly cited as an important risk factor for spontaneous abortion. For humans, however, there is little physiological evidence linking miscarriage to stress. This lack of evidence may be attributable to a paucity of research on maternal stress during the earliest gestational stages. Most human studies have focused on “clinical” pregnancy (&gt;6 weeks after the last menstrual period). The majority of miscarriages, however, occur earlier, within the first 3 weeks after conception (≈5 weeks after the last menstrual period). Studies focused on clinical pregnancy thus miss the most critical period for pregnancy continuance. We examined the association between miscarriage and levels of maternal urinary cortisol during the first 3 weeks after conception. Pregnancies characterized by increased maternal cortisol during this period (within participant analyses) were more likely to result in spontaneous abortion ( P &lt; 0.05). This evidence links increased levels in this stress marker with a higher risk of early pregnancy loss in humans.