First live birth after uterus transplantation in the United States.

Uterus transplantation has proven to be a successful treatment for women with absolute uterine infertility, caused either by the absence of a uterus or the presence of a nonfunctioning uterus. We report the first birth of a healthy child following uterus transplantation in the United States, from a recipient of a uterus allograft procured from an altruistic living donor. Two major modifications from the previously reported live births characterized this uterus transplant. First, the transplanted uterus relied upon and sustained the pregnancy while having only the utero-ovarian vein as venous outflow. The implication is a significantly simplified living donor surgery that paves the way for minimally invasive laparoscopic or robot-assisted techniques for the donor hysterectomy. Second, the time from transplantation to embryo transfer was significantly shortened from prior protocols, allowing for an overall shorter exposure to immunosuppression by the recipient and lowering the risk for potential adverse effects from these medications.

Living Donor Uterus Transplantation: A Single Center's Observations and Lessons Learned From Early Setbacks to Technical Success.

Uterus transplantation is a vascularized composite allograft transplantation. It allows women who do not have a uterus to become pregnant and deliver a baby. In this paper, we analyze the first five cases of living donor uterus transplantation performed in the United States. The first three recipients lost their uterus grafts at days 14, 12, and 6, respectively, after transplant. Vascular complications, related to both inflow and outflow problems, were identified as the primary reason for the graft losses. Two recipients, at 6 and 3 mo, respectively, after transplant, have functioning grafts with regular menstrual cycles. Ultimate success will be claimed only after a live birth. This paper is an in-depth analysis of evaluation, surgical technique, and follow-up of these five living donor uterus transplants. The lessons learned were instrumental in allowing us to evolve from failure to technical and functional success. We aim to share our conclusions and build on knowledge in the evolving field of uterus transplantation.

Can Anti-Müllerian Hormone levels predict future pregnancy outcomes in recurrent pregnancy loss?

OBJECTIVE: Serum Anti-Müllerian Hormone (AMH) levels have been shown to be lower among women who have experienced recurrent pregnancy loss (RPL) compared with the general population. However, it is unclear whether it can predict livebirth. This study aims to determine whether AMH can predict the likelihood of a livebirth in women with RPL. STUDY DESIGN: Prospective analysis of a consecutive cohort of women undergoing investigation for RPL in a tertiary referral centre over a seven year period (August 2014 -December 2021). Analysis was performed using descriptive statistics, chi-square models and logistic regression models adjusting for maternal age and previous livebirth. Exclusion criteria for the regression analysis included abnormal parental karyotype and abnormal pelvic ultrasound scan. Pregnancy outcome was defined as livebirth or further pregnancy loss. RESULTS: There were 488 women who underwent investigation of RPL during the study period. Of these, 65.2% (n = 318) conceived following attendance at the clinic. The majority of these women (69.4%, n = 221) proceeded to have a livebirth. There were no differences in median AMH levels between the livebirth group and the further pregnancy loss group (11 pmol/L vs 9 pmol/L respectively (p = 0.083). AMH did not affect clinical pregnancy rates (p = 0.77, 95% CI = 0.99 [0.98, 1.01]) or pregnancy outcome (p = 0.30, 95% CI = 1.01 [0.99, 1.04]). Abnormal pelvic ultrasonography (p = 0.04) and an abnormal parental karyotype (p = 0.04) were associated with an increased likelihood of a subsequent pregnancy loss. CONCLUSION: Although AMH levels may have some utility in counselling of some couples with RPL, these contemporaneous data indicate that low AMH does not negatively influence subsequent pregnancy outcome in women with recurrent pregnancy loss.

Is perinatal substance abuse falling through the cracks?

OBJECTIVES: Perinatal substance abuse (PSA) is associated with increased risk of prematurity, low birth weight, neonatal abstinence syndrome, behavioral issues and learning difficulties. It is imperative that robust care pathways are in place for these high-risk pregnancies and that staff and patient education are optimized. The present study explores the knowledge and attitudes of healthcare professionals toward PSA to identify knowledge gaps to enhance care and reduce stigma. METHODS: This is a cross-sectional study using questionnaires to survey healthcare professionals (HCPs) working in a tertiary maternity unit (n = 172). RESULTS: The majority of HCPs were not confident in the antenatal management (75.6%, n = 130) or postnatal management (67.5%, n = 116) of PSA. More than half of HCPs surveyed (53.5%, n = 92) did not know the referral pathway and 32% (n = 55) did not know when to make a TUSLA referral. The vast majority (96.5%, n = 166) felt that they would benefit from further training, and 94.8% (n = 163) agreed or strongly agreed that the unit would benefit from a drug liaison midwife. Among study participants, 54.1% (n = 93) agreed or strongly agreed that PSA should be considered a form of child abuse and 58.7% (n = 101) believe that the mother is responsible for damage done to her child. CONCLUSIONS: Our study highlights the urgent need for increased training on PSA to enhance care and reduce stigma. It is imperative that staff training, drug liaison midwives and dedicated clinics are introduced to hospitals as a matter of high priority.

Eye malformations in rats: induction by prenatal exposure to nickel carbonyl.

Exposure of pregnant rats to inhalation of nickel carbonyl on days 7 or 8 of gestation frequently causes the progeny to develop ocular anomalies, including anophthalmia and microphthalmia. The incidence of extraocular anomalies is very low. The specificity of nickel carbonyl for induction of ocular anomalies in rats appears to be unique among known teratogenic agents.

Expression, purification and preliminary crystallographic analysis of Pseudomonas aeruginosa RocR protein.

Pseudomonas aeruginosa RocR, an EAL-domain protein which regulates the expression of virulence genes and biofilm formation, has been cloned and expressed in Escherichia coli and purified. Here, the crystallization and preliminary diffraction analysis of RocR are reported. The X-ray diffraction data were processed to a resolution of 2.50 A. The crystals belonged to space group P6(1)22 or P6(5)22, with unit-cell parameters a = 118.8, b = 118.8, c = 495.1 A, alpha = beta = 90, gamma = 120 degrees .

A locus and mechanism of action for associative morphine tolerance.

Repeated administration of an opioid in the presence of specific environmental cues can induce tolerance specific to that setting (associative tolerance). Prolonged or repeated administration of an opioid without consistent contextual pairing yields non-associative tolerance. Here we demonstrate that cholecystokinin acting at the cholecystokinin-B receptor is required for associative but not non-associative morphine tolerance. Morphine given in the morphine-associated context increased Fos-like immunoreactivity in the lateral amygdala and hippocampal area CA1. Microinjection of the cholecystokinin B antagonist L-365,260 into the amygdala blocked associative tolerance. These results indicate that cholecystokinin acting in the amygdala is necessary for associative tolerance to morphine's analgesic effect.

The Prx1 homeobox gene is critical for molar tooth morphogenesis.

The paired-related homeobox genes, Prx1 and Prx2, encode transcription factors critical for orofacial development. Prx1(-/-)/Prx2(-/-) neonates have mandibular hypoplasia and malformed mandibular incisors. Although the mandibular incisor phenotype has been briefly described (ten Berge et al., 1998, 2001; Lu et al., 1999), very little is known about the role of Prx proteins during tooth morphogenesis. Since the posterior mandibular region was relatively normal, we examined molar tooth development in Prx1(-/-)/Prx2(-/-) embryos to determine whether the tooth malformation is primary to the loss of Prx protein or secondary to defects in surrounding tissues. Three-dimensional (3D) morphological reconstructions demonstrated that Prx1(-/-)/Prx2(-/-) embryos had molar malformations, including cuspal changes and ectopic epithelial projections. Although we demonstrate that Prx1 protein is expressed only mesenchymally, 3D reconstructions showed important morphological defects in epithelial tissues at the cap and bell stages. Analysis of these data suggests that the Prx homeoproteins are critical for mesenchymal-epithelial signaling during tooth morphogenesis.

Induction of testicular sarcomas in Fischer rats by intratesticular injection of nickel subsulfide.

Nickel subsulfide (Ni3S2) was injected in various amounts into the testis of adult Fischer rats for the study of the acute and chronic effects of Ni3S2 on testicular cells. Rats given injections of 0.6 to 10 mg of Ni3S2 developed an immediate inflammatory response at the site of injection, followed by a delayed, slowly evolving coagulation necrosis of seminiferous tubules and interstitial cells. The extent of testicular necrosis was dose dependent, but at doses of 5 or 10 mg of Ni3S2 the rats invariably developed subtotal destruction of the testis. The testis became atrophic, without regeneration of seminiferous tubules. No damage was seen in the other testis, and no systemic effects were noted. Malignant testicular neoplasms developed in 16 of 19 rats within 20 months after an injection of 10 mg of Ni3S2. These neoplasms were classified by light and electron microscopy as fibrosarcomas, malignant fibrous histiocytomas, and rhabdomyosarcomas. None of the testicular neoplasms was derived from germ cells or genital cord cells. The occurrence of rhabdomyosarcomas in the testis, an organ normally devoid of striated muscle, suggests that Ni3S2 induces malignant transformation of undifferentiated, pluripotential mesenchymal cells.

The effect of maternal and child early life factors on grade repetition among HIV exposed and unexposed children in rural KwaZulu-Natal, South Africa.

Receiving an education is essential for children living in poverty to fulfil their potential. Success in the early years of schooling is important as children who repeat grade one are particularly at risk for future dropout. We examined early life factors associated with grade repetition through logistic regression and explored reasons for repeating a grade through parent report. In 2012-2014 we re-enrolled children aged 7-11 years in rural KwaZulu-Natal who had been part of an early life intervention. Of the 894 children included, 43.1% had repeated a grade, of which 62.9% were boys. Higher maternal education (aOR 0.44; 95% CI 0.2-0.9) and being further along in the birth order (aOR 0.46; 95% CI 0.3-0.9) reduced the odds of grade repetition. In addition, maternal HIV status had the strongest effect on grade repetition for girls (aOR 2.17; 95% CI 1.3-3.8), whereas for boys, it was a fridge in the household (aOR 0.59; 95% CI 0.4-1.0). Issues with school readiness was the most common reason for repeating a grade according to parental report (126/385, 32.7%), while school disruptions was an important reason among HIV-exposed boys. Further research is needed to elucidate the pathways through which HIV affects girls' educational outcomes and potentially impacts on disrupted schooling for boys. Our results also highlight the importance of preparation for schooling in the early years of life; future research could focus on gaining a better understanding of mechanisms by which to improve early school success, including increased quality of reception year and investigating the protective effect of older siblings.

Access to bone marrow transplantation for leukemia and lymphoma: the role of sociodemographic factors.

PURPOSE: Use of bone marrow transplantation (BMT), a complex, costly treatment for many forms of cancers, has increased significantly in recent years. The increasingly competitive health care marketplace raises concerns about patient access to costly medical procedures such as BMT. We attempted to evaluate patient access to BMT for the treatment of leukemias and lymphomas. METHODS: We analyzed inpatient hospital discharge data from four states (California, Maryland, Massachusetts, and New York) for 2 years (1988 and 1991) to examine whether the use of BMT for patients with either leukemia or lymphoma varies by sociodemographic characteristics and insurance coverage. We developed a sorting algorithm to collapse the discharge data into patient level records. We used logistic regression to analyze the odds of receiving a BMT stratified by disease type (leukemia or lymphoma). RESULTS: After controlling for other factors, black patients with leukemia are 51% to 53% as likely as whites, while black patients with lymphoma are 34% to 45% as likely as white patients to undergo a BMT (P < .05). Medicaid, self-pay patients, and Health Maintenance Organization (HMO) enrollees with either leukemia or lymphoma are significantly less likely to undergo a BMT compared with patients with private insurance. Younger patients are significantly more predisposed to undergo a BMT than older patients. The odds of receiving a BMT have increased over time, but the rates of increase vary by state. Consistent with clinical expectations, the relative odds of BMT vary significantly by type of leukemia or lymphoma. CONCLUSION: Substantial variation exists in access to BMT for patients with either leukemia or lymphoma. Black patients, those enrolled in HMOs, those covered by Medicaid, and self-pay patients were less likely to receive a BMT when admitted for either leukemia or lymphoma. These findings raise concerns about access to cancer treatments for patients in the current health care system.

Differential access in the receipt of antiretroviral drugs for the treatment of AIDS and its implications for survival.

BACKGROUND: Recently published research based on selected samples of patients treated at human immunodeficiency virus clinics documents that use of more intensive antiretroviral drug therapies is responsible for significant declines in morbidity and mortality in persons living with human immunodeficiency virus or acquired immunodeficiency syndrome (PLWHAs). In this study, we evaluate whether receipt of more recently developed antiretroviral therapies varies by sex and race/ethnicity in a large population-based sample of PLWHAs and whether receipt of such drugs has any impact on survival. METHODS: Analysis of Florida Medicaid eligibility, enrollment, and claims data for PLWHAs for 1993 through 1997. Receipt of 2 nucleoside analogs (TWONUKES) and receipt of 1 protease inhibitor and a nucleoside combination (PI+NUKES) was constructed from claims data. The probability of dying was constructed from eligibility and enrollment data. RESULTS: The probabilities of receiving TWONUKES and PI+NUKES are 0.16 and 0.09, respectively, lower for women relative to men (P<.01 for both). Blacks are more likely to receive TWONUKES than whites, whereas the reverse is true for Hispanics; this probability is almost 0.04 higher for blacks and 0.03 lower for Hispanics relative to whites (P<.01). In contrast, blacks are significantly less likely to receive PI+NUKES (P<.01). Both drug variables have large statistically significant negative effects on the probability of death. The PLWHAs who received PI+NUKES are 60% as likely to die each month (P<.01). Receipt of TWONUKES lowers the relative hazard of death by close to 66% each month (P<.01). Survival varies significantly by sex and race/ethnicity. Controlling for receipt of drug therapy and diagnosed health throughout the period, women are 56% as likely to die as men (P<.01). Hispanics are almost 14% less likely to die each month relative to whites (relative hazard, 0.87), and blacks are 20% more likely to die than whites (relative hazard, 1.21). CONCLUSIONS: States need to investigate why women are less likely to receive antiretroviral drug therapies than men and to consider policies that might foster better access to antiretroviral therapies for women with acquired immunodeficiency syndrome because these efforts might yield even further reductions in mortality in women. Given the large reductions in mortality that accompany receipt of antiretroviral therapies, states need to foster policies that promote widespread use of new drug treatment protocols.

Physicians' ethical beliefs about cost-control arrangements.

BACKGROUND: Although much has been written about the ethics of new methods of health care financing, little is known about the extent to which physicians experience these cost-control arrangements as ethical problems. METHOD: A cross-sectional telephone survey of 1,549 physicians, 8 to 17 years after residency, randomly selected from 75 US metropolitan service areas (response rate, 74.0%). RESULTS: Only 17.0% believed that financial incentives to limit services are ethically acceptable. Although 52.9% thought that physicians should try to abide by guidelines discouraging the use of interventions with possible but unproven benefit, only 14.5% thought such guidelines should be enforced by payers. Only 5.7% thought that it was morally acceptable for payers to discourage physicians from telling patients about their personal financial incentives, and only 9.1% found compliance with such restrictions morally acceptable. Changes in the health care system in the past 5 years were believed to have had a negative impact on their own patients' trust in them by 50.6%, and 80.8% believed that changes in the health care system in the past decade have diminished physicians' commitment to an ethic of undivided loyalty to patients. In multiple regression analysis, physicians who reported that the overall personal financial incentives in their practices encouraged them to reduce services were significantly more likely to have ethical objections to such incentives, to believe their own patients' trust in them had diminished, and to believe that the ethic of undivided loyalty to patients had diminished. CONCLUSIONS: Many of the methods now commonly used to influence medical decision making are considered ethically objectionable by most midcareer physicians. Whether their ethical disquiet about these arrangements is justified cannot be answered from these data.

Brainstem pain modulating circuitry is sexually dimorphic with respect to mu and kappa opioid receptor function.

We have previously shown that activation of kappa opioid receptors within the rostral ventral medulla in lightly anesthetized rats has an anti-mu opioid analgesic action in male rats. Microinjections of the kappa opioid receptor agonist, U69593, attenuated the increase in tail-flick latency produced by activation of mu opioid receptors located within the ventrolateral periaqueductal gray. There are sex differences in the pain modulating potency of opioid analgesics, including kappa opioid agonists. In the present study, we examined whether activation of kappa opioid receptors within the rostral ventral medulla in lightly anesthetized female rats produces an anti-mu opioid analgesic effect similar to that found in males. We found that in the RVM the same dose of kappa opioid receptor agonist that reduces mu receptor-mediated increase in tail-flick latency in male rats produces a moderate increase in tail-flick latency in female rats. Additionally, we discovered that female rats are significantly more sensitive to the mu opioid agonist, DAMGO, injected into the ventrolateral periaqueductal gray. The results indicate that these two brain structures, which mediate the analgesic effects of opioids, are sexually dimorphic with regard to opioid receptor function.

The contribution of the rostral ventromedial medulla to the antinociceptive effects of systemic morphine in restrained and unrestrained rats.

Although there are numerous opioid-sensitive structures in the central nervous system, the contribution of each to the analgesic effect of systemically administered morphine is controversial. One such structure is the rostral ventromedial medulla. In the present study, we tested the hypothesis that the rostral ventromedial medulla is necessary for the full expression of systemic morphine-induced antinociception. Additionally, we examined whether the modulatory effect of the rostral ventromedial medulla on tail-flick latency is dependent on the behavioral state of the animal. In unrestrained rats, inactivation of the rostral ventromedial medulla with either lidocaine (0.5 microl of 4%) or muscimol (50 ng) had no effect on tail-flick latency. In contrast, in restrained rats, inactivation of the rostral ventromedial medulla with either lidocaine (0.5 microl of 4%) or muscimol (50 ng) significantly decreased tail-flick latency. In both conditions, microinjection of morphine (5 microg) into this region significantly increased tail-flick latency. Additionally, in unrestrained rats, muscimol (50 ng) and cholecystokinin tetrapeptide (0.5 ng) infusion into the rostral ventromedial medulla completely reversed systemic morphine-induced analgesia, while lidocaine (0.5 microl of 4%) and cholecystokinin octapeptide (0.25 ng) infusion partially reversed systemic morphine-induced analgesia. These findings demonstrate that the rostral ventromedial medulla does not tonically modulate tail-flick latency in unrestrained rats, but does modulate tail-flick latency when animals are stressed via restraint. These findings also strongly support the hypothesis that the rostral ventromedial medulla is necessary for the full analgesic effects of systemically administered morphine.

Substantial work disability and earnings losses in individuals less than age 65 with osteoarthritis: comparisons with rheumatoid arthritis.

Substantial earnings losses and work disability were seen in individuals less than age 65 with asymmetric oligoarthritis, a surrogate for osteoarthritis, almost as great as those seen with symmetric polyarthritis, a surrogate for rheumatoid arthritis. The proportions of individuals who were working was 66.7% for men and 35.5% for women with asymmetric oligoarthritis, compared to 56.1% and 31.0% of those with symmetric polyarthritis, and 89.4 and 61.6% of those with no arthritis. Rates of work disability in individuals with asymmetric oligoarthritis involving one knee or one hip were in the same range as those in individuals with symmetric polyarthritis involving two knees or two hips. The earnings of women and men with asymmetric oligoarthritis were only 30 and 63% respectively of the earnings of persons with no arthritis. However, less than one-third of these earnings losses were explained by the presence of arthritis, with further explanation from higher age, lower formal education levels, and comorbidity in individuals with asymmetric oligoarthritis. These results suggest that greater attention to demographic and comorbidity variables may be indicated in efforts to control economic losses associated with arthritis.

Augmented femoral venous return.

We present a technique of femoral cardiopulmonary bypass that allows excellent venous drainage. This is accomplished by augmenting the venous return with a centrifugal pump.

Continuous retrograde blood cardioplegia.

We present a technique of myocardial protection using retrograde cold blood cardioplegia. This safe and simple method allows excellent continuous and homogeneous cooling of the heart during the ischemic period in all types of open heart operations.

Effects of case management and new drugs on Medicaid AIDS spending.

This study evaluates the effects of Florida's participation in the Medicaid acquired immunodeficiency syndrome (AIDS) home and community-based waiver and the use of recently developed AIDS drugs on spending per Medicaid beneficiary. We find that monthly Medicaid spending for waiver non-participants was significantly higher than was spending for waiver nonparticipants. The major reason for the cost difference is that nonwaiver enrollees incurred significantly higher inpatient costs than did those enrolled in the waiver. Although waiver enrollees had higher drug spending, these represent only a fraction of the higher inpatient costs incurred by nonwaiver enrollees. Thus, it appears that adherence to appropriate medications reduces the need for inpatient care. The case management approach of the AIDS waiver may have similar effects for persons with other chronic diseases.

Effects of HMO market penetration on physicians' work effort and satisfaction.

We investigate whether geographic variations in health maintenance organization (HMO) market penetration are associated with three aspects of physicians' practices: number of hours worked per year, number of patients seen per week, and satisfaction with the current practice. Based on multivariate regression analysis of data for 4,373 patient care physicians (under age forty-five) from a national random sample surveyed in 1991, we estimate that a doubling of the average level of HMO penetration is associated with statistically significant differences of 4 percent fewer annual hours, 13.7 percent fewer patients seen per week, and a 20 percent greater likelihood of not being very satisfied with one's current practice.