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Chromosomal mosaicism, or the co-existence of cells with different chromosomal content, is a phenomenon that has been documented in human embryos for three decades. Early versions of preimplantation genetic testing (PGT-A) did not measure mosaicism, either because typically only a single cell was assessed, or because the technique could not accurately identify it. While this led to a straightforward diagnosis (an embryo was considered either normal or abnormal), it simply avoided the matter and in hindsight may have led to numerous misdiagnoses with negative clinical consequences. Modern PGT-A evaluates a multicellular biopsy with technologies capable of recognizing intermediate copy number signals for chromosomes or sub-chromosomal regions. We are therefore inevitably confronted with the issue of mosaicism and the challenge of managing embryos producing such results in the clinic. Here we discuss recent data showing that not only mosaicism in general, but specific features of mosaicism detected with PGT-A are associated with variable clinical outcomes. The conclusion is evident: mosaicism should be considered for more informed and improved embryo selection in the clinic.

Emergence from anesthesia can be associated with a wide spectrum of cognitive and behavioral dysregulation in children, including delirium or acute brain dysfunction. This period of neurobehavioral recovery can be further confounded by pain, anxiety, and fear. The implementation of monitoring for level of consciousness, pain, and delirium using valid pediatric tools is necessary to avoid misdiagnosis due to overlapping symptomatology and support appropriate management. Understanding the epidemiology of delirium in the postoperative setting will require consistent use of accurate terminology in the medical literature. The current interchangeable use of the terms "emergence agitation" and "emergence delirium" needs to be highlighted and awareness of differences in patient conditions and assessment tools is essential. We discuss epidemiology of emergence agitation and delirium in the pediatric population, and the challenges for future delineation of monitoring and management. Furthermore, we describe the possible impact of long-term consequences of emergence delirium among infants and children, and the necessary areas of future research.

Extra or missing chromosomes—a phenomenon termed aneuploidy—frequently arises during human meiosis and embryonic mitosis and is the leading cause of pregnancy loss, including in the context of in vitro fertilization (IVF). While meiotic aneuploidies affect all cells and are deleterious, mitotic errors generate mosaicism, which may be compatible with healthy live birth. Large-scale abnormalities such as triploidy and haploidy also contribute to adverse pregnancy outcomes, but remain hidden from standard sequencing-based approaches to preimplantation genetic testing (PGT-A). The ability to reliably distinguish meiotic and mitotic aneuploidies, as well as abnormalities in genome-wide ploidy may thus prove valuable for enhancing IVF outcomes. Here, we describe a statistical method for distinguishing these forms of aneuploidy based on analysis of low-coverage whole-genome sequencing data, which is the current standard in the field. Our approach overcomes the sparse nature of the data by leveraging allele frequencies and linkage disequilibrium (LD) measured in a population reference panel. The method, which we term LD-informed PGT-A (LD-PGTA), retains high accuracy down to coverage as low as 0.05× and at higher coverage can also distinguish between meiosis I and meiosis II errors based on signatures spanning the centromeres. LD-PGTA provides fundamental insight into the origins of human chromosome abnormalities, as well as a practical tool with the potential to improve genetic testing during IVF.Significance StatementWhole chromosome gains and losses—termed aneuploidies—are the leading cause of human pregnancy loss and congenital disorders. Recent work has demonstrated that in addition to harmful meiotic aneuploidies, mitotic aneuploidies (which lead to mosaic embryos harboring cells with different numbers of chromosomes) may also be common in preimplantation embryos but potentially compatible with healthy birth. Here we developed and tested a method for distinguishing these forms of aneuploidy using genetic testing data from 8154 IVF embryos. We re-classified embryos based on signatures of meiotic and mitotic error, while also revealing lethal forms of chromosome abnormality that were hidden to existing approaches. Our method complements standard protocols for preimplantation and prenatal genetic testing, while offering insight into the biology of early development.

Miscarriage is generally defined as the loss of a pregnancy before viability. An estimated 23 million miscarriages occur every year worldwide, translating to 44 pregnancy losses each minute. The pooled risk of miscarriage is 15·3% (95% CI 12·5–18·7%) of all recognised pregnancies. The population prevalence of women who have had one miscarriage is 10·8% (10·3–11·4%), two miscarriages is 1·9% (1·8–2·1%), and three or more miscarriages is 0·7% (0·5–0·8%). Risk factors for miscarriage include very young or older female age (younger than 20 years and older than 35 years), older male age (older than 40 years), very low or very high body-mass index, Black ethnicity, previous miscarriages, smoking, alcohol, stress, working night shifts, air pollution, and exposure to pesticides. The consequences of miscarriage are both physical, such as bleeding or infection, and psychological. Psychological consequences include increases in the risk of anxiety, depression, post-traumatic stress disorder, and suicide. Miscarriage, and especially recurrent miscarriage, is also a sentinel risk marker for obstetric complications, including preterm birth, fetal growth restriction, placental abruption, and stillbirth in future pregnancies, and a predictor of longer-term health problems, such as cardiovascular disease and venous thromboembolism. The costs of miscarriage affect individuals, health-care systems, and society. The short-term national economic cost of miscarriage is estimated to be £471 million per year in the UK. As recurrent miscarriage is a sentinel marker for various obstetric risks in future pregnancies, women should receive care in preconception and obstetric clinics specialising in patients at high risk. As psychological morbidity is common after pregnancy loss, effective screening instruments and treatment options for mental health consequences of miscarriage need to be available. We recommend that miscarriage data are gathered and reported to facilitate comparison of rates among countries, to accelerate research, and to improve patient care and policy development.

The Bone Morphogenetic Proteins (BMPs) are the largest class signaling molecules within the greater Transforming Growth Factor Beta (TGFβ) family, and are responsible for a wide array of biological functions, including dorsal-ventral patterning, skeletal development and maintenance, as well as cell homeostasis. As such, dysregulation of BMPs results in a number of diseases, including fibrodysplasia ossificans progressiva (FOP) and pulmonary arterial hypertension (PAH). Therefore, understanding BMP signaling and regulation at the molecular level is essential for targeted therapeutic intervention. This review discusses the recent advances in the structural and biochemical characterization of BMPs, from canonical ligand-receptor interactions to co-receptors and antagonists. This work aims to highlight how BMPs differ from other members of the TGFβ family, and how that information can be used to further advance the field. Lastly, this review discusses several gaps in the current understanding of BMP structures, with the aim that discussion of these gaps will lead to advancements in the field.

Aneuploidy is the leading contributor to pregnancy loss, congenital anomalies, and in vitro fertilization (IVF) failure in humans. Although most aneuploid conceptions are thought to originate from meiotic division errors in the female germline, quantitative studies that link the observed phenotypes to underlying error mechanisms are lacking. In this study, we developed a mathematical modeling framework to quantify the contribution of different mechanisms of erroneous chromosome segregation to the production of aneuploid eggs. Our model considers the probabilities of all possible chromosome gain/loss outcomes that arise from meiotic errors, such as nondisjunction (NDJ) in meiosis I and meiosis II, and premature separation of sister chromatids (PSSC) and reverse segregation (RS) in meiosis I. To understand the contributions of different meiotic errors, we fit our model to aneuploidy data from 11,157 blastocyst-stage embryos. Our best-fitting model captures several known features of female meiosis, for instance, the maternal age effect on PSSC. More importantly, our model reveals previously undescribed patterns, including an increased frequency of meiosis II errors among eggs affected by errors in meiosis I. This observation suggests that the occurrence of NDJ in meiosis II is associated with the ploidy status of an egg. We further demonstrate that the model can be used to identify IVF patients who produce an extreme number of aneuploid embryos. The dynamic nature of our mathematical model makes it a powerful tool both for understanding the relative contributions of mechanisms of chromosome missegregation in human female meiosis and for predicting the outcomes of assisted reproduction.

Less than half of human zygotes survive to live birth, primarily due to aneuploidies of meiotic or mitotic origin. Mitotic errors lead to chromosomal mosaicism, defined by multiple cell lineages with distinct chromosome complements. The incidence and fitness consequences of chromosomal mosaicism in human embryos remain controversial, with most previous studies based on bulk DNA assays or comparisons of multiple biopsies of a few embryonic cells. Single-cell genomic data provide an opportunity to quantify mosaicism on an embryo-wide scale. To this end, we extended an approach to infer aneuploidies based on chromosome dosage-associated changes in gene expression by integrating signatures of allelic imbalance. We applied this method to published single-cell RNA sequencing data from 74 disaggregated human embryos, spanning the morula to blastocyst stages. Our analysis revealed widespread mosaic aneuploidies across preimplantation development, with 59 of 74 (80%) embryos harboring at least one aneuploid cell (1% FDR). By clustering copy number calls, we reconstructed histories of chromosome mis-segregation, distinguishing meiotic and early mitotic errors from those occurring after lineage differentiation. We observed no significant enrichment of aneuploid cells in the trophectoderm compared to the inner cell mass, though we do detect such an enrichment in published data from later post-implantation stages. Finally, we observed that aneuploid cells exhibit upregulation of immune response genes, as well as downregulation of genes involved in proliferation, metabolism, and protein processing, consistent with stress responses previously documented in other stages and systems. Together, our work provides a high-resolution view of aneuploidy in preimplantation embryos and supports the conclusion that low-level mosaicism is a common feature of early human development.

Background Fatigue occurs in 75%–95% of people with multiple sclerosis (MS) and is frequently reported as the most disabling symptom. A multicomponent group program of six weekly 2-hour sessions, Fatigue: Take Control (FTC), was developed from an international MS fatigue management guideline. Objective To determine whether FTC is associated with greater improvements in fatigue than MS: Take Control (MSTC), a similarly structured general MS education program. Methods This four-site, parallel, single-blind, randomized controlled trial compared FTC and MSTC in 204 ambulatory participants with MS. The primary outcome, the Modified Fatigue Impact Scale (MFIS), and secondary outcomes of self-efficacy, physical activity, sleep, and medications were assessed at baseline, program completion, and 3 and 6 months later. Results Mean MFIS scores improved in both groups between baseline and program completion (FTC −4.4, p < 0.001; MSTC −3.8, p < 0.001), between baseline and 3 months after program completion (FTC −3.2, p = 0.01; MSTC −3.3, p = 0.01), and between baseline and 6 months after program completion (FTC −5.2, p < 0.001; MSTC −4.8, p < 0.001). These improvements were not statistically different between groups ( p = 0.64, 0.92, and 0.82, respectively). Conclusion Participation in FTC modestly improved self-reported fatigue for up to 6 months. This improvement did not differ significantly from that occurring with the control program.

Along with errors in meiosis, mitotic errors during post-zygotic cell division contribute to pervasive aneuploidy in human embryos. Relatively little is known, however, about the genesis of these errors or their fitness consequences. Rapid technological advances are helping to close this gap, revealing diverse molecular mechanisms contributing to mitotic error. These include altered cell cycle checkpoints, aberrations of the centrosome, and failed chromatid cohesion, mirroring findings from cancer biology. Recent studies are challenging the idea that mitotic error is abnormal, emphasizing that the fitness impacts of mosaicism depend on its scope and severity. In light of these findings, technical and philosophical limitations of various screening approaches are discussed, along with avenues for future research.

Understanding fertility in young and old Fertility in humans follows a U-curve, with low rates in both teenagers and women of advancing maternal age (mid-30s and above). Gruhn et al. found that this distinct shape originates from chromosomal errors in human eggs, which result in genomic imbalance and pregnancy loss. The error types and chromosomes affected in the young and advanced age groups were different, suggesting that two distinct chromosome-based mechanisms balance risk associated with pregnancy and evolutionary fitness as women enter and exit their reproductive life span. The authors show that chromosome structure erodes only with advancing age, acting as a “molecular clock” for reproductive senescence. Science , this issue p. 1466

Background Mycobacterium leprae was thought to be the exclusive causative agent of leprosy until Mycobacterium lepromatosis was identified in a rare form of leprosy known as diffuse lepromatous leprosy (DLL). Methods We isolated M. lepromatosis from a patient with DLL and propagated it in athymic nude mouse footpads. Genomic analysis of this strain (NHDP-385) identified a unique repetitive element, RLPM, on which a specific real-time quantitative polymerase chain reaction assay was developed. The RLPM assay, and a previously developed RLEP quantitative polymerase chain reaction assay for M. leprae, were validated as clinical diagnostic assays according to Clinical Laboratory Improvement Amendments guidelines. We tested DNA from archived histological sections, patient specimens from the United States, Philippines, and Mexico, and US wild armadillos. Results The limit of detection for the RLEP and RLPM assays is 30 M. leprae per specimen (0.76 bacilli per reaction; coefficient of variation, 0.65%–2.44%) and 122 M. lepromatosis per specimen (3.05 bacilli per reaction; 0.84%–2.9%), respectively. In histological sections (n = 10), 1 lepromatous leprosy (LL), 1 DLL, and 3 Lucio reactions contained M. lepromatosis; 2 LL and 2 Lucio reactions contained M. leprae; and 1 LL reaction contained both species. M. lepromatosis was detected in 3 of 218 US biopsy specimens (1.38%). All Philippines specimens (n = 180) were M. lepromatosis negative and M. leprae positive. Conversely, 15 of 47 Mexican specimens (31.91%) were positive for M. lepromatosis, 19 of 47 (40.43%) were positive for M. leprae, and 2 of 47 (4.26%) contained both organisms. All armadillos were M. lepromatosis negative. Conclusions The RLPM and RLEP assays will aid healthcare providers in the clinical diagnosis and surveillance of leprosy.

Because preoperative risk factor modification is generally not possible in the emergency setting, complication prevention represents an important focus for quality improvement in emergency general surgery (EGS). The objective of our study was to determine the overall impact that specific postoperative complications have in this patient population.Our study sample consisted of patients from the 2012-2013 ACS-NSQIP database who underwent an EGS procedure. We used population attributable fractions (PAFs) to estimate the overall impact that each of 8 specific complications had on 30-day physiologic and resource use outcomes in our study population. The PAF represents the percentage reduction in a given outcome that would be anticipated if a complication were able to be completely prevented in our study population. Both unadjusted and risk-adjusted PAFs were calculated.There were 79,183 patients included for analysis. The most common complications in these patients were bleeding (6.2%), incisional surgical site infection (SSI) (3.4%), pneumonia (2.7%), and organ/space SSI (2.6%). Bleeding was the complication with the greatest overall impact on mortality and end-organ dysfunction, demonstrating an adjusted PAF of 10.7% (95% CI 8.2%,13.1%, p0.001) and 15.9% (95% CI 13.9%, 16.7%, p 0.001) for these respective outcomes. The only other complication with a sizeable impact on these outcomes was pneumonia (adjusted PAF of 7.9% for mortality and 13.2% for pneumonia). In contrast, complications such as urinary tract infection, venous thromboembolism, myocardial infarction, and incisional SSI had negligible impacts on these outcomes.Our study provides a framework for the development of high-value quality initiatives in EGS.

STUDY QUESTION\ud Is a clinical trophectoderm (TE) biopsy a suitable predictor of chromosomal aneuploidy in blastocysts?\ud \ud SUMMARY ANSWER\ud In the analyzed group of blastocysts, a clinical TE biopsy was an excellent representative of blastocyst karyotype in cases of whole chromosome aneuploidy, but in cases of only segmental (sub-chromosomal) aneuploidy, a TE biopsy was a poor representative of blastocyst karyotype.\ud \ud WHAT IS KNOWN ALREADY\ud Due to the phenomenon of chromosomal mosaicism, concern has been expressed about the possibility of discarding blastocysts classified as aneuploid by preimplantation genetic testing for aneuploidy (PGT-A) that in fact contain a euploid inner cell mass (ICM). Previously published studies investigating karyotype concordance between TE and ICM have examined small sample sizes and/or have utilized chromosomal analysis technologies superseded by Next Generation Sequencing (NGS). It is also known that blastocysts classified as mosaic by PGT-A can result in healthy births. TE re-biopsy of embryos classified as aneuploid can potentially uncover new instances of mosaicism, but the frequency of such blastocysts is currently unknown.\ud \ud STUDY DESIGN, SIZE, DURATION\ud For this study, 45 patients donated 100 blastocysts classified as uniform aneuploids (non-mosaic) using PGT-A by NGS (n = 93 whole chromosome aneuploids, n = 7 segmental aneuploids). In addition to the original clinical TE biopsy used for PGT-A, each blastocyst was subjected to an ICM biopsy as well as a second TE biopsy. All biopsies were processed for chromosomal analysis by NGS, and karyotypes were compared to the original TE biopsy.\ud \ud PARTICIPANTS/MATERIALS, SETTING, METHODS\ud The setting for this study was a single IVF center with an in-house PGT-A program and associated research laboratory.\ud \ud MAIN RESULTS AND THE ROLE OF CHANCE\ud When one or more whole chromosomes were aneuploid in the clinical TE biopsy, the corresponding ICM was aneuploid in 90 out of 93 blastocysts (96.8%). When the clinical TE biopsy contained only segmental (sub-chromosomal) aneuploidies, the ICM was aneuploid in three out of seven cases (42.9%). Blastocysts showing aneuploidy concordance between clinical TE biopsy and ICM were also aneuploid in a second TE biopsy in 86 out of 88 cases (97.7%). In blastocysts displaying clinical TE–ICM discordance, a second TE biopsy was aneuploid in only two out of six cases (33.3%).\ud \ud LIMITATIONS, REASONS FOR CAUTION\ud All embryos in this study had an initial classification of ‘aneuploid’ and not ‘euploid’ or ‘mosaic’. Therefore, the findings of this study refer specifically to a TE biopsy predicting aneuploidy in the remaining blastocyst, and cannot be extrapolated to deduce the ability of a TE biopsy to predict euploidy in the blastocyst. No conclusions should be drawn from this study about the ability of a mosaic TE biopsy to predict the karyotype of the corresponding blastocyst. Caution should be exercised in generalizing the findings of the sample group of this study to the general IVF blastocyst population. The segmental aneuploidy group only contained seven samples.\ud \ud WIDER IMPLICATIONS OF THE FINDINGS\ud The high rate of intra-blastocyst concordance observed in this study concerning whole chromosome aneuploidy contributes experimental evidence to the validation of PGT-A at the blastocyst stage. Concomitantly, the results suggest potential clinical value in reassessing blastocysts deemed aneuploid by TE re-biopsy in select cases, particularly in instances of segmental aneuploidies. This could impact infertility treatment for patients who only have blastocysts classified as aneuploid by PGT-A available.\ud \ud STUDY FUNDING/COMPETING INTEREST(S)\ud This study was supported by the Zouves Foundation for Reproductive Medicine and Zouves Fertility Center. The authors have no competing interest to disclose.

Objectives To assess the association of the Pharmacists' Pneumonia Prevention Program (PPPP) with changes in beliefs related to pneumonia vaccination (PV) in a predominately older African American population. Methods PPPP was an educational intervention delivered using a senior center model of care consisting of a formal pharmacist presentation, live skit, small group action planning, and optional PV. A 15-item instrument assessed participants' beliefs at baseline, post-test, and three months across four domains: pharmacists and pharmacies, vaccination, pneumococcal disease, and physicians. Friedman tests and pairwise Wilcoxon signed rank tests were used to determine the statistical significance of the mean change in belief responses across timepoints. Results 190 older adults participated; the sample was majority female (76.3%) and African American (80.5%), and had a mean age of 74.3 years. Statistically significant improvements in beliefs at post-test were observed in the following domains: pharmacists and pharmacies, vaccination, and the pneumococcal disease; however, some of these gains were incompletely sustained at three months. Conclusion PPPP positively impacted beliefs post-program regarding the pneumococcal disease, pharmacists and pharmacies, and vaccination; however, sustained efforts may be needed to reinforce these gains. Policy implications Support for pharmacist educational services in senior centers should be considered.

Objective\ud To investigate the parameters of mosaicism and the biological mechanisms leading to healthy pregnancies from mosaic embryo transfers.\ud \ud Design\ud Prospective study.\ud \ud Setting\ud IVF center and associated research laboratory.\ud \ud Patient(s)\ud Fifty-nine patients.\ud \ud Intervention(s)\ud Embryos underwent blastocyst-stage preimplantation genetic testing for aneuploidy by next-generation sequencing. Trophectoderm biopsies containing 20%–80% abnormal cells were deemed mosaic, and corresponding blastocysts were transferred. Mosaic embryos donated to research were examined for karyotype concordance in multiple biopsies and assessed for cell proliferation and death by immunofluorescence and computational quantitation.\ud \ud Main Outcome Measure(s)\ud Chemical start of pregnancy, implantation, fetal heartbeat, and birth.\ud \ud Result(s)\ud Globally, mosaic embryos showed inferior clinical outcomes compared with euploid embryos. Aneuploid cell percentage in trophectoderm biopsies did not correlate with outcomes, but type of mosaicism did, as embryos with single mosaic segmental aneuploidies fared better than all other types. Mosaic blastocysts generated from oocytes retrieved at young maternal ages (?34 years) showed better outcomes than those retrieved at older maternal ages. Mosaic embryos displayed low rates of karyotype concordance between multiple biopsies and showed significant elevation of cell proliferation and death compared with euploid embryos.\ud \ud Conclusion(s)\ud After euploid embryos, mosaic embryos can be considered for transfer, prioritizing those of the single segmental mosaic type. If a patient has mosaic embryos available that were generated at different ages, preference should be given to those made at younger ages. Intrablastocyst karyotype discordance and differential cell proliferation and death might be reasons that embryos classified as mosaic can result in healthy pregnancies and babies.

Introduction A number of clinical trials have reported improved IVF outcomes when embryos are previously vetted for chromosomal aneuploidies, and yet a significant percentage of euploid embryos still fail to implant. Conversely, there is mounting evidence of mosaic embryos leading to pregnancies, and there even exist anecdotal reports of aneuploid embryos resulting in healthy births. Critics of PGT- A point out that a TE biopsy might not correctly represent the entire blastocyst. Genetic discordance between TE and ICM could severely affect the clinical outcomes of PGT-A. Furthermore, a blastocyst classified as aneuploidy might in reality contain a euploid ICM, which could lead to discarding potentially viable embryos in IVFclinics. To date, studies addressing the question of concordance between TE and ICM have relied oncurrently superseded technologies and/or small sample sizes. Here we analyze 100 blastocysts that wereclassified as aneuploid by PGT-A, probing the genetic makup of their paired ICMs using high-resolutionNextGen Sequencing (hr-NGS). Materials & methods We optimized a method to collect ICM biopsies that are free of TE cell contamination, validated by immunofluorescence for lineage markers. Using this technique we isolated ICM biopsies from 100 blastocysts that had previously undergone clinical PGT-A, and had displayed aneuploidy in their TE biopsies (93 whole chromosome aneuploids and 7 segmental aneuploids). All samples were analyzed by hr-NGS, and resulting karyotype profiles of TE and ICM biopsies were compared. We also developed a bioinformatics approach based on SNP analysis and imputation to confirm that the biopsies of blastocysts with TE-ICM discordance indeed stemmed from the same embryo, excluding the possibility of sample mix-up or contamination. Results Comparison of 100 paired TE-ICM karyotypes revealed that a clinical TE biopsy correctly predicts aneuploidy in the ICM in the vast majority of cases. When one or more whole chromosomes were aneuploid in the clinical TE biopsy, the corresponding ICM was aneuploid in 90 out of 93 blastocysts (96.8%). Nonetheless, when the clinical TE biopsy only contained segmental (sub- chromosomal) aneuploidies, the ICM was aneuploid in only 3 out of 7 cases (43%). Combined, and when all types of aneuploidy were considered, an aneuploid TE biopsy correctly predicted aneuploidy in the ICM in 93 outof 100 cases. Of the 7 out of 100 blastocysts that were TE-ICM discordant, the ICM was mosaic in 2 casesand euploid in 5 cases. A second TE biopsy collected from the 7 TE-ICM discordant blastocysts showedconcordance with the original clinical TE biopsy in only 2 out of 7 cases (28%). Conclusions These findings suggest that TE biopsy, in our hands, largely predicts the chromosome constitution of the ICM and this has significant clinical implications. Concomitantly, the results suggest clinical value of reevaluatingblastocysts deemed ‘aneuploid’ in select cases by TE re-biopsy, particularly in instances of segmental aneuploidies.

Background: Vaccination is the best way to prevent pneumococcal disease (PD), but 40% of older adults remain unvaccinated nationwide, with even greater nonvaccination rates among African Americans (AAs). Prior studies suggest that insufficient knowledge contributes to low vaccination rates. The Pharmacists’ Pneumonia Prevention Program (PPPP) was designed to improve older adults’ knowledge about PD and pneumococcal vaccination (PV). Objective: To measure PPPP’s effect on knowledge and activation in a predominantly AA population and determine program costs. Methods: PPPP uses a senior center model with a pharmacist presentation, actors’ skit, and small-group action planning. Knowledge about PD risk, transmission, symptoms, and PV side effects was assessed at baseline (BL), postintervention (PT), and 3 months (M3) and analyzed using an intention-to-treat (ITT) approach. Actions taken (got vaccinated, spoke to doctor or pharmacist, discussed with family/friends) were assessed at M3. PPPP costs ($US 2013) included staff time, PV, actor, and site fees. Results: Of 276 attending PPPP, 190 consented and were included in the ITT sample, which was largely black (80.5%) and female (76.3%) and had a mean age of 74.4 years. Knowledge improved by 46.8% (BL vs PT), with significant gains in all domains. At M3, knowledge improved by 54.2% vs BL, indicating sustained gains; 37.2% of previously unvaccinated participants reported receiving PV by M3. Program cost was $119 per attendee. Conclusion: PPPP significantly improved PD and PV knowledge. It could be delivered more efficiently by holding larger events on fewer dates, staffing with volunteers where appropriate, and utilizing a local pharmacy to manage the vaccine supply.

Aneuploidy is prevalent in human preimplantation embryos and is the leading cause of pregnancy loss. Many aneuploidies arise during oogenesis, increasing in frequency with maternal age. Superimposed on these meiotic aneuploidies are a range of errors occurring during early mitotic divisions of the embryo, contributing to widespread chromosomal mosaicism. Here we reanalyzed a published dataset comprising preimplantation genetic testing for aneuploidy in 24,653 blastomere biopsies from day-3 cleavage-stage embryos, as well as 17,051 trophectoderm biopsies from day-5 blastocysts. We focused on complex abnormalities that affected multiple chromosomes simultaneously, seeking to quantify their incidences and gain insight into their mechanisms of formation. In addition to well-described patterns such as triploidy and haploidy, we identified 4.7% of day-3 blastomeres possessing karyotypes suggestive of tripolar mitosis in normally-fertilized diploid zygotes or descendant diploid cells. We further supported this hypothesis using time-lapse data from an intersecting set of 77 cleavage-stage embryos. The diploid tripolar signature was rare among day-5 blastocyst biopsies (0.5%), suggesting that complex aneuploidy generated by tripolar mitosis impairs cellular and/or early embryonic survival. Strikingly, we found that the tripolar mitosis mechanism is responsible for the previously described association with common maternal genetic variants spanning PLK4. Our findings are consistent with the role of PLK4 as the master regulator of centriole duplication with a known capacity to induce tripolar mitosis when mutated or mis-expressed. Taken together, we propose that tripolar mitosis is a key mechanism generating karyotype-wide aneuploidy in cleavage-stage embryos and implicate PLK4-mediated centrosome abnormality as a factor influencing its occurrence.

PURPOSE: This study aimed to determine if patients with infertility or recurrent pregnancy loss have higher rates of embryo aneuploidy than fertile controls. METHODS: This was a retrospective review of all pre-implantation genetic screening (PGS) cases processed by a single reference lab prior to March 2014 after a blastocyst biopsy. Cases were excluded if no indication for PGS was designated or patients were translocation carriers. The fertile control group consisted of patients undergoing IVF with PGS for sex selection only. The comparison cohorts included those with recurrent pregnancy loss, male factor infertility, unexplained infertility, prior failed IVF, or previous aneuploid conceptions. A quasi-binomial regression model was used to assess the relationship between the dependent variable, aneuploidy rate and the independent variables, maternal age and reason for PGS. A quasi-Poisson regression model was used to evaluate the relationship between similar independent variables and the number of blastocyst biopsies per case. RESULTS: The initial study population consisted of 3378 IVF-PGS cycles and 18,387 analyzed trophectoderm samples. Controlling for maternal age, we observed an increased rate of aneuploidy among patients with recurrent pregnancy loss (OR 1.330, p 0.05). The increase in aneuploidy in patients with RPL and prior IVF failure was driven by both an increase in meiotic (OR 1.488 and 1.508, p

Assisted reproductive technologies (ART) have become the standard of care for the treatment of infertility. Within this realm, reliable prediction of the developmental potential of the pre‐implantation human embryo remains an overriding priority. One such technology, pre‐implantation genetic screening (PGS), is being increasingly deployed to select against embryonic aneuploidy [1]. However, a growing number of seemingly contradictory outcome reports are forcing a reevaluation of this approach. Here, we discuss how biological factors, notably mitotic aneuploidy during early embryonic development, limit the very rationale for PGS as a clinical diagnostic method. > … PGS is an example of technology compromised by biology The development of safe and efficient methods to select healthy euploid embryos constitutes a pressing need to improve the success of ART. PGS, as one strategy to achieve this, relies on the ploidy status of the trophectoderm layer of the blastocyst‐stage embryo [1] (Table 1). Considerable numbers of patients are undergoing PGS: In the USA alone, more than 5% of 106,902 non‐donor assisted reproduction cycles resorted to PGS during 2011 and 2012 [2]. However, the capacity of PGS to select euploid embryos has recently been questioned by the birth of healthy newborns whose originating blastocysts were deemed mosaic (euploid–aneuploid) [3]. Similar inconsistencies have previously been reported for euploid human embryonic stem cell lines, which have been derived from purportedly aneuploid blastocysts. We suggest herein that the utility of PGS is undermined by innate karyotypic mosaicism, the ontogeny and significance of which in early human development remain uncertain. Viewed in this light, PGS is an example of technology compromised by biology. It follows that the ability of PGS to reliably predict the ploidy status of the human embryo and its developmental potential is limited. View this table: Table 1. Blastocyst developmental potential as inferred from the PGS biopsy ploidy status ### The causes of embryonic aneuploidy Following fertilization and karyogamy, the human zygote undergoes 8–9 …

Testosterone enanthate (TE) administration attenuates bone loss in orchiectomized (ORX) rats. However, testosterone administration may increase risk for prostate/lower urinary tract related adverse events and polycythemia in humans. Trenbolone enanthate (TREN) is a synthetic testosterone analogue that preserves bone mineral density (BMD) and results in less prostate enlargement than testosterone in young ORX rodents. The purpose of this experiment was to determine if intramuscular TREN administration attenuates bone loss and maintains bone strength, without increasing prostate mass or hemoglobin concentrations in skeletally mature ORX rodents. Forty, 10 month old male F344/Brown Norway rats were randomized into SHAM, ORX, ORX+TE (7.0 mg/week), and ORX+TREN (1.0 mg/week) groups. Following surgery, animals recovered for 1 week and then received weekly: vehicle, TE, or TREN intramuscularly for 5 weeks. ORX reduced total and trabecular (t) BMD at the distal femoral metaphysis compared with SHAMs, while both TREN and TE completely prevented these reductions. TREN treatment also increased femoral neck strength by 28% compared with ORX animals (p

The path of a thrown ball is one of many examples that can connect middle school math to calculus. Showing this calculus connection early may motivate students to undertake increasingly advanced high school and college math.

Objectives: Report results of a randomized-clinical trial of the efficacy of periodontal care in the improvement of glycemic control in 165 veterans with poorly controlled diabetes over 4 months. Methods: Outcomes were change in Haemoglobin A1c (HbAlc) in the Early Treatment versus untreated (Usual Care) groups and percent of participants with decreases in HbAlc. Analyses included simple/multiple variable linear/logistic regressions, adjusted for baseline HbAlc, age, and duration of diabetes. Results: Unadjusted analyses showed no differences between groups. After adjustment for baseline HbAlc, age, and diabetes duration, the mean absolute HbAlc change in the Early Treatment group was - 0.65% versus - 0.51% in the Usual Care group (p = 0.47). Adjusted odds for improvement by 0.5% in the Early Treatment group was 1.67 (95% confidence interval: 0.84, 3.34, p = 0.14). Usual Care subjects were twice as likely to increase insulin from baseline to 4 months (20% versus 11%, p = 0.12) and less likely to decrease insulin (1% versus 6%, p = 0.21) than Early Treatment subjects. Among insulin users at baseline, more increased insulin in the Usual Care group (40% versus 21%, p = 0.06). Conclusions: No significant benefit was found for periodontal therapy after 4 months in this study; trends in some results were in favour of periodontal treatment.

Objective To determine the effect of maternal age on the average number of euploid embryos retrieved during oocyte harvest as part of an in vitro fertilization (IVF) cycle, including the probability of retrieving at least one euploid embryo in a cohort (PrE). Design Retrospective study. Setting Preimplantation genetic screening (PGS) laboratory. Patient(s) Women aged 18 to 48 years undergoing IVF treatment. Intervention(s) Use of 24-chromosome single-nucleotide polymorphism (SNP)-based PGS of day-3 and day-5 embryo biopsies. Main Outcome Measure(s) Relationships between maternal age and the rate of embryos that tested as euploid (hereafter referred to as "euploid embryos"), the average number and proportion of euploid embryos per IVF cycle, and PrE. Result(s) We analyzed 22,599 day-3 embryos and 15,112 day-5 embryos. In women aged 27 to 35 years, the median proportion of euploid embryos in each cycle remained constant at ∼35% in day-3 biopsies and ∼55% in day-5 biopsies, but it decreased rapidly after age 35. On average, women in their late 20s had four euploid embryos (day 3 or day 5) per cycle, but this number decreased linearly (R 2 ≥ 0.983) after 35 years of age. The effect of maternal age on PrE was similar, with a rapid exponential decline (R 2 = 0.986). Across all maternal ages, the euploid proportion and number of embryos per cycle were counterbalanced, so the number of euploid embryos per cycle was the same for day-3 and day-5 biopsies. This suggests that the loss of embryos from day 3 to day 5 was primarily due to aneuploidy. Conclusion(s) Our results confirm the known inverse relationship between advanced maternal age (>35 years) and embryo euploidy, demonstrating that equal numbers of euploid embryos are available at day 3 and day 5.

Whole-chromosome imbalances affect over half of early human embryos and are the leading cause of pregnancy loss. While these errors frequently arise in oocyte meiosis, many such whole-chromosome abnormalities affecting cleavage-stage embryos are the result of chromosome missegregation occurring during the initial mitotic cell divisions. The first wave of zygotic genome activation at the 4–8 cell stage results in the arrest of a large proportion of embryos, the vast majority of which contain whole-chromosome abnormalities. Thus, the full spectrum of meiotic and mitotic errors can only be detected by sampling after the initial cell divisions, but prior to this selective filter. Here, we apply 24-chromosome preimplantation genetic screening (PGS) to 28,052 single-cell day-3 blastomere biopsies and 18,387 multi-cell day-5 trophectoderm biopsies from 6,366 in vitro fertilization (IVF) cycles. We precisely characterize the rates and patterns of whole-chromosome abnormalities at each developmental stage and distinguish errors of meiotic and mitotic origin without embryo disaggregation, based on informative chromosomal signatures. We show that mitotic errors frequently involve multiple chromosome losses that are not biased toward maternal or paternal homologs. This outcome is characteristic of spindle abnormalities and chaotic cell division detected in previous studies. In contrast to meiotic errors, our data also show that mitotic errors are not significantly associated with maternal age. PGS patients referred due to previous IVF failure had elevated rates of mitotic error, while patients referred due to recurrent pregnancy loss had elevated rates of meiotic error, controlling for maternal age. These results support the conclusion that mitotic error is the predominant mechanism contributing to pregnancy losses occurring prior to blastocyst formation. This high-resolution view of the full spectrum of whole-chromosome abnormalities affecting early embryos provides insight into the cytogenetic mechanisms underlying their formation and the consequences for human fertility., Author Summary By day 3 of development, more than half of human embryos contain at least one cell that deviates from the typical 46-chromosome complement. These whole-chromosome abnormalities include polyploidies, which affect the entire chromosome set, as well as aneuploidies, which involve gains and losses of particular chromosomes. The rate of aneuploidy increases with maternal age, primarily due to chromosome segregation errors arising during egg formation (maternal meiosis). While some forms of aneuploidy, such as Trisomy 21, are compatible with live birth, most aneuploid embryos do not survive to term. Our study applied genetic techniques to screen early embryos from in vitro fertilization cycles, demonstrating that while diverse whole-chromosome abnormalities can be observed at early developmental stages, these errors are strongly filtered during preimplantation development. Specifically, errors occurring during the initial post-fertilization cell divisions often result in the simultaneous loss of multiple chromosomes, a pattern consistent with abnormal cell division. Our data provide evidence of selection against this class of aneuploidy before day 5 of development, thus reducing fertility. Patients referred for genetic screening due to previous IVF failure had higher rates of mitotic error, highlighting its clinical relevance and indicating that patient-specific genetic and environmental factors influence error rates.

Chromosome number varies in humans Pregnancy loss is often associated with a loss of chromosome number, a condition known as aneuploidy. When examining aneuploid embryos during in vitro fertilization cycles, McCoy et al. found a large genomic region associated with defects in maternal chromosome number (see the Perspective by Vohr and Green). This region contains a gene, Polo-like Kinase 4 ( PLK4 ), that is known to affect chromosome segregation and has variants that correlate with an increased rate of maternal aneuploidy. Surprisingly, such variants occur at relatively high levels in human populations and may be under positive selection. Science , this issue p. 235 ; see also p. 180

The third National Health and Nutrition Examination Survey was utilized to assess serum rubella immunoglobulin G antibody titers in a representative sample of American children. Antibody titers were significantly lower in children with a history of seizures and in children treated for seizures compared to unaffected children, after adjustment for age, ethnicity, residence, and region ( P =0.022 and 0.029, respectively). Children with the lowest antibody titers were non-Hispanic whites who had a history of seizures. The percentage of US adolescents and young adults with a history of seizures that may have insufficient immunity to rubella is estimated to be 14–50%.

Controversy exists over how long trials of nonoperative management should be pursued in patients with uncomplicated adhesive small bowel obstructions (ASBOs) before deciding to proceed with surgery. The purpose of this study was to determine the effect of incremental delays in surgery on the 30-day postoperative outcomes of patients undergoing surgery for uncomplicated ASBO.American College of Surgeons National Surgical Quality Improvement Program 2005-2011 data were used to identify patients with uncomplicated ASBO in whom a trial of nonoperative management was attempted. Multivariate logistic or linear regression model was created to determine the independent association between the length of preoperative hospitalization and 30-day postoperative outcomes after adjustment for patient- and procedure-related factors.A total of 9,297 patients were included in the study. The 30-day postoperative mortality and overall morbidity rates of the entire cohort were 4.4% and 29.6%, respectively. The median postoperative length of hospitalization was 7 days (interquartile range, 5-11 days). After risk adjustment, there was no association between preoperative length of hospitalization and 30-day postoperative mortality. In contrast, increased 30-day overall morbidity was observed in patients who received their operation after a preoperative length of hospitalization of 3 days compared with earlier in their hospitalization. Furthermore, an increased postoperative length of hospitalization was found in patients who were operated on after a preoperative length of hospitalization of 4 days.Trials of nonoperative management for uncomplicated ASBO exceeding 3 days are associated with increased morbidity and postoperative length of hospitalization. These trials should therefore generally not extend beyond this time point.Therapeutic study, level IV.

Known as “Valley Fever,” coccidiomycosis is a soil-borne, fungal infection predominately found in endemic regions of the southwestern United States and Latin America. While most infected individuals are asymptomatic, An 11-year-old boy presented with a 7-month history of left anterior knee pain. Physical examination revealed mild knee effusion and quadriceps atrophy with focal tenderness to palpation to the distal pole of the patella. Laboratory studies were unre-markable and plain radiographs revealed a radiolucency in the inferomedial aspect of the patella. Magnetic resonance imaging revealed a corresponding focus of increased T2 signal with sclerotic margins and peripheral edema within the patella. Open biopsy with curettage confirmed coccidiomycosis, and the patient was successfully managed with long-term antifungal antibiotics. To our knowledge, this article presents the first known case of coccidioidal osteomyelitis of the patella.

An aneurysm of the vein of Galen is a rare arteriovenous malformation of the central nervous system. Fetal manifestations have included nonimmune hydrops, hydrocephalus, and intracranial hemorrhage. This anomaly may be diagnosed prenatally by several imaging modalities. A cystic cranial mass was identified by ultrasound in a fetus at 30 weeks gestation. Both pulsed-wave Doppler and color-velocity imaging studies suggested aneurysm of the vein of Galen was the most likely diagnosis. The fetus demonstrated no evidence of hydrops on serial ultrasound examinations. A 2430 g female infant was delivered vaginally at 35 weeks gestation. Postnatal management included transarterial embolization of the vessels feeding the aneurysm with craniectomy, an intra-aneurysmal balloon, and vascular microcoils. Hydrocephalus developed and a ventriculo-peritoneal shunt was placed. The infant has grown appropriately in the first year of life. An aneurysm of the vein of Galen may be diagnosed prenatally by real-time ultrasound, pulsed-wave Doppler, color-velocity imaging, or magnetic resonance imaging. The presence of this malformation should prompt close follow-up for the remainder of the pregnancy. Careful obstetric management and early postnatal intervention may lead to a favorable outcome.

Lead (Pb) poisoning of a pregnant heifer was diagnosed based upon clinical signs (head pressing, blindness, muscle twitching) and a blood lead concentration of 1.73 ppm. Blood and urinary Pb half-lives with CaNa2 EDTA/thiamine therapy were determined to be 2.08 and 1.38 days, respectively. Many cations (Ca, Fe, Zn, Na, Cu), including Pb, were excreted at higher concentrations in urine during therapy. Blood (0.425 ppm) and liver (4.85 ppm) Pb concentrations in the fetus were 71.7% and 84.3% of the same tissue Pb concentrations of the dam, indicating a significant transfer of Pb in utero. Severe polioencephalomalacia was described in the adult, and hepatic lysosomes with metallic electron densities were present in the fetus.

Background : Fetal lymphangiomas can occur in many different anatomic locations, including the most commonly seen nuchal cystic hygroma. Case : A fetus at 18 weeks' gestation was found to have a massive right axillary hygroma. The fetal karyotype was normal. Serial ultrasound examinations indicated progressive enlargement, but no hydrops. At 32 weeks' gestation, a left axillary hygroma was also diagnosed. The patient underwent cesarean delivery. Conclusion : Prenatal diagnosis of nuchal cystic hygromas has a high association with karyotypic abnormalities, hydrops, and fetal demise; however, this association may not apply to cystic lymphangiomas at other locations.

Objective To analyze the etiologies and outcomes for a southeastern section of the United States, and to organize an efficient approach to evaluation. Methods We reviewed 82 cases of non-immune hydrops presenting after 20 weeks' gestation over a 10-year period. Results Overall perinatal mortality was 86.6%. Fetuses diagnosed with hydrops before 24 weeks' gestation had a perinatal mortality of 95%, with nearly one-third having abnormal karyotypes. The etiology of hydrops diagnosed after 24 weeks' gestation was more likely to remain idiopathic or to be related to cardiothoracic abnormalities. Conclusion Before 24 weeks' gestation, the high risk of mortality and abnormal karyotype justifies offering families funipuncture in the hope of finding a treatable cause of non-immune hydrops. After 24 weeks' gestation, when fewer abnormal karyotypes are found, funipuncture may also be pivotal in diagnosing the cause of non-immune hydrops.

We evaluated the pregnancy outcome of all patients with elevations of both maternal serum alpha-fetoprotein and human chorionic gonadotropin since institution of combined serum screening at our program. After analysis of 34,404 samples, 99 patients were found to have significant elevations of both maternal serum alpha-fetoprotein and human chorionic gonadotropin. The ultrasound findings, amniocentesis results, and pregnancy outcomes were determined in each case. Sixty-six patients with singleton gestations met entry criteria. Pregnancy outcome information is available for 63 of these patients, 60% of whom had at least one complication. Thirty-three patients with multiple gestations met inclusion criteria. Pregnancy outcome information is available for 31 of these, 81% of whom had at least one complication. These patients had a high incidence of pregnancy related complications. This group would appear to be at higher risk than women with elevation of either maternal serum alpha-fetoprotein or human chorionic gonadotropin alone.

Background In preclinical studies, müllerian inhibiting substance (MIS) has a protective affect against breast cancer. Our objective was to determine whether serum MIS concentrations were associated with cancerous or precancerous lesions. Blood from 30 premenopausal women was collected and serum extracted prior to their undergoing breast biopsy to assess a suspicious lesion found on imaging or physical examination. Based on biopsy results, the serum specimens were grouped as cancer (invasive or ductal carcinoma in situ), precancer (atypical hyperplasia or lobular carcinoma in situ), or benign. Findings Serum from women with cancer and precancer (p = .0009) had lower MIS levels than serum from women with benign disease. Conclusion Our findings provide preliminary evidence for MIS being associated with current breast cancer risk, which should be validated in a larger population.

Hypothyroidism usually presents insidiously with symptoms such as fatigue, cold intolerance, and weight gain. Less common findings include myalgia, arthralgia, and joint effusion. In the patient described here, a triathlete, interpretation of early signs and symptoms as typical tendinitis led to months of treatment failure. Considering hypothyroidism in the differential diagnosis for patients who have overuse syndromes can expedite treatment. Definitive diagnosis rests on testing of serum thyroid hormone levels. Treatment, which is usually quickly effective, consists of gradually adjusted thyroid hormone replacement.

Predictive tests for the identification of women at high risk of the development of preeclampsia are critical to allow the most appropriate preventive measures. Preeclampsia is a vasospastic condition of pregnancy characterized by early and enhanced vascular reactivity to endogenous pressor agents. Exercise tolerance testing with cycle ergometry to induce hemodynamic response measured with duplex Doppler A/B ratio of the umbilical artery could unmask latent vascular pressor hypersensitivity. Our prospective cohort study was designed to test the efficacy of the American College of Obstetricians and Gynecologists exercise in pregnancy guidelines for the low-risk atheletic, physically active, or sedentary patient. The pattern of fetal response to material exercise testing at 28 weeks' gestation was compared with subsequent maternal mean arterial blood pressure and the development of pregnancy-induced hypertension and preeclampsia. Doppler A/B ratio during the recovery period was assessed as below baseline (18) or elevated above resting baseline values (12). Third-trimester blood pressure pattern was assessed to be elevated in 11 patients, 10 of whom had elevated recovery A/B ratios. The Fisher exact test results were ( p = 0.00002) positive predictive value, 83%; negative predictive value, 94%; sensitivity, 91%; and specificity, 89%. Preeclampsia developed in four patients; all had elevated recovery A/B ratios. Fisher exact test results were ( p = 0.01806) positive predictive value, 33%; negative predictive value, 100%; sensitivity, 100%; and specificity, 69%.

Abdominal aortic aneurysms (AAAs) are a rare entity in the pediatric population. Children with mycotic (infectious) AAA in particular are at risk of life-threatening rupture due to their rapid expansion coupled with aortic wall thinning and deterioration. Here, we present the case of a 10-month-old infant with prior 2-staged repair for hypoplastic left heart syndrome that was incidentally discovered to have a mycotic AAA on abdominal ultrasound (US) for evaluation of renovascular hypertension. Before the time of evaluation with US, the infant had developed methicillin-resistant Staphylococcus aureus bacteremia 3 days after cardiac catheterization with percutaneous thoracic aortic balloon angioplasty. She had normal aortic contours on contrasted computed tomography scan of the abdomen approximately 2 weeks before the aforementioned US evaluation. This infant subsequently underwent open aneurysmorrhaphy with cryopreserved vein patch angioplasty with resolution of her aneurysmal segment.

The effects of a lower-extremity progressive resistance-training program (PRT) on risk factors for coronary artery disease (CAD) were determined in patients with multiple sclerosis (MS). Twelve ambulatory women with MS (47.3+/-4.7 years; Expanded Disability Status Score (EDSS), 4.00+/-1.37) completed twice weekly lower-body PRT for 8 weeks. Knee extensor and ankle flexor strength improved significantly (p0.05) after training, and self-reported fatigue decreased (p0.05). Serum triglyceride concentrations decreased (p0.05) but body-weight and fatness, blood pressure, and serum glucose, total cholesterol and high-density lipoprotein cholesterol were unchanged. However, the number of CAD risk factors that reached the clinical threshold for each subject declined after PRT, suggesting that resistance training can promote CAD risk reduction in ambulatory female MS subjects.

The association between fetal parvovirus B19 infection and hydrops was first reported in 1984. The virus has a predilection for the erythroid cell line, which in the fetus may produce anemia. Recent cases of parvovirus infection in other fetal cell lines have raised concern that the infection may induce fetal anomalies in rare cases. We report two pregnancies complicated by parvovirus B19 infection. In each instance the patient had normal second trimester ultrasounds but subsequently developed fetal abnormalities--disruptions of normal structure. One infant has myocardial infarction, splenic calcifications, and mild hydrocephalus. The other had moderate hydrocephalus with central nervous system scarring. There are two possible mechanisms in which parvovirus may induce fetal anomalies. Both direct infection of fetal organs and vascular inflammation have been documented in association with B19 parvovirus. Although fetal abnormalities associated with parvovirus are rare, continued study of this organism may indicate a greater pathologic potential than is now thought.

Little is known about the relationship between intramyocellular lipid (IMCL) and coronary artery disease (CAD)/non-insulin-dependent diabetes mellitus risk factors. The aim of the study was to examine the relationship between IMCL and CAD/non-insulin-dependent diabetes mellitus risk factors in healthy male (n = 9) and female (n = 10) subjects with similar norm-based aerobic fitness and body composition. Nineteen volunteers (21-36 years) completed health and physical activity questionnaires, cardiovascular and body composition evaluation, and assessment of thigh IMCL using proton magnetic resonance spectroscopy. Outcome measures were blood pressure, total cholesterol, high-density lipoprotein cholesterol, C-reactive protein, interleukin 6, tumor necrosis factor alpha (TNF-alpha), homocysteine, insulin resistance (IR), percentage of body fat, waist-to-hip ratio, physical activity levels, and cardiovascular fitness. Analysis of variance was used for group comparisons. Correlation analyses were used to determine association between variables, and stepwise regression was used to determine predictive variables of IR. Women had 2-fold higher IMCL and greater IR than men (P < .05). Men had greater plasma homocysteine and interleukin 6 concentration (P < .05) as well as stronger correlations with CAD risk factors than female subjects. Correlation analyses using all subjects revealed a significant relationship between IMCL and waist-to-hip ratio, body weight, percentage of body fat, and IR. In the regression analysis, age, IMCL, and TNF-alpha were the strongest predictors of IR (R2 = 0.62, P < .01). Our results suggest that female subjects, matched for age and fitness, have higher IMCL compared with their male counterparts. IMCL was correlated with several CAD and prediabetes markers in both male and female subjects. In the final regression model, age, IMCL, and TNF-alpha were the strongest predictors of IR. Future studies with larger sample sizes are warranted.

Alpha1-antitrypsin deficiency is an inherited pulmonary disorder which results from a deficiency of a major plasma protease inhibitor. The onset and severity of symptoms vary widely and depend on the genotype and whether the patient smokes cigarettes. Alpha1-antitrypsin in pregnancy has only been previously reported twice. Our patient had a functional serum alpha1-antitrypsin level which was 15% of normal but was clinically asymptomatic and she did not smoke. Her genotype revealed a non-ZZ pattern. Her obstetric history was complicated by preterm labor in each of her five ongoing pregnancies. Alpha1-antitrypsin deficiency is inherited via two codominant autosomal genes. Although there is great variability in severity of disease, seriously affected patients may have emphysema and hepatic abnormalities. Patients with non-ZZ genotypes or who are heterozygotes may have favorable pregnancy outcomes.