Direct Oral Anticoagulant Use Early After Cardiac Surgery: A Retrospective Cohort Study.

Background: There is limited literature guiding the prescribing of direct oral anticoagulants (DOACs) early after cardiac surgery as this population has been excluded from landmark randomized controlled trials. This study aims to determine the rate of in-hospital DOAC use compared with warfarin early after cardiac surgery, evaluate factors associated with DOAC use, determine difference in postoperative length of stay, and characterize bleeding events. Methods: A retrospective cohort study was conducted in adult patients with indications for anticoagulation and receiving either a DOAC or warfarin after cardiac surgery during their index hospitalization. Patients were excluded if they had any contraindications to DOAC use. The primary outcome was the proportion of patients discharged on a DOAC compared with warfarin. Results: Of included 210 patients, 30% received DOACs and 70% received warfarin on discharge. The most common DOAC used was apixaban (74.6%), and median postoperative day of initiation was 5 days. Patients receiving DOACs were older (70.8 vs 68.0 years), had less valvular heart disease (38.1% vs 63.9%), were more likely to be on DOACs preoperatively (50.8% vs 31.3%), and were more likely to have undergone coronary artery bypass graft alone (54.0% vs 24.5%) compared with those on warfarin. Postoperative length of stay (7 vs 9 days; P = 0.59) and in-hospital bleeding (1.6% vs 2.0%; P = 1.00) did not differ between DOAC and warfarin groups. Conclusions: At a quaternary referral centre for cardiac surgery, DOACs were used in approximately one-third of patients with an indication for anticoagulation early after cardiac surgery.

Introduction: Il existe peu de documentation sur la prescription des anticoagulants oraux directs (AOC) peu de temps après la chirurgie cardiaque puisque cette population a été exclue des essais cliniques novateurs à répartition aléatoire. La présente étude vise à déterminer le taux d'utilisation des AOC à l'hôpital par rapport au taux d'utilisation de la warfarine peu de temps après la chirurgie cardiaque, à évaluer les facteurs associés à l'utilisation des AOC, à déterminer l'écart de la durée du séjour et à caractériser les événements hémorragiques. Méthodes: Nous avons réalisé une étude de cohorte rétrospective auprès de patients adultes qui avaient des indications d'anticoagulation et qui recevaient des AOC ou de la warfarine après la chirurgie cardiaque durant l'hospitalisation de référence. Les patients étaient exclus s'ils avaient des contre-indications à l'utilisation des AOC. Le critère d'évaluation principal était la proportion de patients sortis de l'hôpital sous AOC par rapport à celle des patients sortis de l'hôpital sous warfarine. Résultats: Parmi les 210 patients inclus, 30 % ont reçu des AOC et 70 % ont reçu de la warfarine à la sortie de l'hôpital. L'AOC le plus fréquemment utilisé était l'apixaban (74,6 %), et le nombre médian de jours après l'intervention chirurgicale du début du traitement était 5 jours. Les patients qui recevaient les AOC étaient plus âgés (70,8 vs 68,0 ans), avaient moins de cardiopathies valvulaires (38,1 % vs 63,9 %), étaient plus susceptibles de recevoir des AOC avant l'opération (50,8 % vs 31,3 %) et étaient plus susceptibles d'avoir seulement subi un pontage aorto-coronarien (54,0 % vs 24,5 %) que ceux sous warfarine. La durée du séjour postopératoire (7 vs 9 jours ; P = 0,59) et les événements hémorragiques à l'hôpital (1,6 % vs 2,0 % ; P = 1,00) ne différaient pas entre les groupes qui recevaient les AOC et les groupes qui recevaient la warfarine. Conclusions: Dans un centre d'aiguillage de soins quaternaires en chirurgie cardiaque, les AOC ont été utilisés chez environ un tiers des patients qui avaient une indication d'anticoagulation peu de temps après la chirurgie cardiaque.

High-throughput mRNA sequencing of human placenta shows sex differences across gestation.

INTRODUCTION: Fetal sex affects fetal and maternal health outcomes in pregnancy, but this connection remains poorly understood. As the placenta is the route of fetomaternal communication and derives from the fetal genome, placental gene expression sex differences may explain these outcomes. OBJECTIVES: We utilized next generation sequencing to study the normal human placenta in both sexes in first and third trimester to generate a normative transcriptome based on sex and gestation. STUDY DESIGN: We analyzed 124 first trimester (T1, 59 female and 65 male) and 43 third trimester (T3, 18 female and 25 male) samples for sex differences within each trimester and sex-specific gestational differences. RESULTS: Placenta shows more significant sexual dimorphism in T1, with 94 T1 and 26 T3 differentially expressed genes (DEGs). The sex chromosomes contributed 60.6% of DEGs in T1 and 80.8% of DEGs in T3, excluding X/Y pseudoautosomal regions. There were 6 DEGs from the pseudoautosomal regions, only significant in T1 and all upregulated in males. The distribution of DEGs on the X chromosome suggests genes on Xp (the short arm) may be particularly important in placental sex differences. Dosage compensation analysis of X/Y homolog genes shows expression is primarily contributed by the X chromosome. In sex-specific analyses of first versus third trimester, there were 2815 DEGs common to both sexes upregulated in T1, and 3263 common DEGs upregulated in T3. There were 7 female-exclusive DEGs upregulated in T1, 15 female-exclusive DEGs upregulated in T3, 10 male-exclusive DEGs upregulated in T1, and 20 male-exclusive DEGs upregulated in T3. DISCUSSION: This is the largest cohort of placentas across gestation from healthy pregnancies defining the normative sex dimorphic gene expression and sex common, sex specific and sex exclusive gene expression across gestation. The first trimester has the most sexually dimorphic transcripts, and the majority were upregulated in females compared to males in both trimesters. The short arm of the X chromosome and the pseudoautosomal region is particularly critical in defining sex differences in the first trimester placenta. As pregnancy is a dynamic state, sex specific DEGs across gestation may contribute to sex dimorphic changes in overall outcomes.

A systematic review of genome-wide analyses of methylation changes associated with assisted reproductive technologies in various tissues.

IMPORTANCE: Because analytic technologies improve, increasing amounts of data on methylation differences between assisted reproductive technology (ART) and unassisted conceptions are available. However, various studies use different tissue types and different populations in their analyses, making data comparison and integration difficult. OBJECTIVE: To compare and integrate data on genome-wide analyses of methylation differences due to ART, allowing exposure of overarching themes. EVIDENCE REVIEW: All studies undertaking genome-wide analysis of human methylation differences due to ART or infertility in any tissue type across the lifespan were assessed for inclusion. FINDINGS: Seventeen studies were identified that met the inclusion criteria. One study assessed trophectoderm biopsies, 2 first-trimester placenta, 1 first-trimester fetal tissue, 2 term placenta, 7 cord blood, 3 newborn dried blood spots, 1 childhood buccal smears, 1 childhood peripheral blood, and 2 adult peripheral blood. Eleven studies compared tissues from in vitro fertilization (IVF) conceptions with those of unassisted conceptions, 4 compared intracytoplasmic sperm injection with unassisted conceptions, 4 compared non-IVF fertility treatment (NIFT) with unassisted conceptions, 4 compared NIFT with IVF, and 5 compared an infertile population (conceiving via various methods) with an unassisted presumably fertile population. In studies assessing placental tissue, 1 gene with potential methylation changes due to IVF when compared with unassisted conceptions was identified by 2 studies. In blood, 11 potential genes with methylation changes due to IVF compared with unassisted conceptions were identified by 2 studies, 1 of which was identified by 3 studies. Three potentially affected genes were identified by 2 studies involving blood between intracytoplasmic sperm injection and unassisted populations. There were no overlapping genes identified in any tissue type between NIFT and unassisted populations, between NIFT and IVF, or the infertility combined population when compared with the unassisted fertile population. CONCLUSIONS: Comparing studies is challenging due to differing variables between analyses. However, even in similar tissue types and populations, overlapping methylation changes are limited, suggesting that differences due to ART are minimal. RELEVANCE: Information from this systematic review is significant for providers and patients who provide and use ART to understand methylation risks that may be associated with the technology.

Testicular ACE regulates sperm metabolism and fertilization through the transcription factor PPARγ.

Testis angiotensin-converting enzyme (tACE) plays a critical role in male fertility, but the mechanism is unknown. By using ACE C-domain KO (CKO) mice which lack tACE activity, we found that ATP in CKO sperm was 9.4-fold lower than WT sperm. Similarly, an ACE inhibitor (ACEi) reduced ATP production in mouse sperm by 72%. Metabolic profiling showed that tACE inactivation severely affects oxidative metabolism with decreases in several Krebs cycle intermediates including citric acid, cis-aconitic acid, NAD, α-ketoglutaric acid, succinate, and L-malic acid. We found that sperms lacking tACE activity displayed lower levels of oxidative enzymes (CISY, ODO1, MDHM, QCR2, SDHA, FUMH, CPT2, and ATPA) leading to a decreased mitochondrial respiration rate. The reduced energy production in CKO sperms leads to defects in their physiological functions including motility, acrosine activity, and fertilization in vitro and in vivo. Male mice treated with ACEi show severe impairment in reproductive capacity when mated with female mice. In contrast, an angiotensin II receptor blocker (ARB) had no effect. CKO sperms express significantly less peroxisome proliferators-activated receptor gamma (PPARγ) transcription factor, and its blockade eliminates the functional differences between CKO and WT sperms, indicating PPARγ might mediate the effects of tACE on sperm metabolism. Finally, in a cohort of human volunteers, in vitro treatment with the ramipril or a PPARγ inhibitor reduced ATP production in human sperm and hence its motility and acrosine activity. These findings may have clinical significance since millions of people take ACEi daily, including men who are reproductively active.

Patients' Beliefs About Their Cardiovascular Medications After Acute Coronary Syndrome: A Prospective Observational Study.

Background: Adherence to secondary preventive pharmacotherapy after an acute coronary syndrome (ACS) is generally poor and is associated with recurrent cardiovascular events. Patients' beliefs about their medications are a strong predictor of intentional nonadherence. Methods: This prospective, observational study assessed adult patients' beliefs about their post-ACS medications, using the Beliefs About Medicines Questionnaire (BMQ), and adherence, using the Medication Adherence Report Scale (MARS-5) at St. Paul's Hospital in Vancouver, Canada during May-December, 2022. The BMQ and MARS-5 were administered in-hospital and at 4 weeks after discharge. Outcomes included difference in BMQ necessity-concerns differential (BMQ-NCD) from hospitalization to 4-week follow-up and factors associated with the BMQ-NCD. Results: Forty-seven participants completed the 4-week follow-up. The mean age was 64 years, and 83% were male. Most presented with a non-ST-segment-elevation ACS. No difference occurred in BMQ-NCD (7.3 vs 6.6, P = 0.29) or MARS-5 scores from discharge to 4 weeks (22.8 vs 23.7, P = 0.06); however, the BMQ specific-necessity subscale score decreased significantly (20.3 vs 18.8, P = 0.002). South Asian and Middle Eastern ethnic origins, compared to European, were associated with a higher BMQ-NCD. Part-time employment and male sex were associated with a lower BMQ-NCD. Conclusions: Participants held favourable beliefs about their post-ACS medications, which were largely unchanged from hospitalization to 4 weeks postdischarge, except for beliefs about the necessity of taking their medications. Those of European descent, those with part-time employment, and males had the lowest BMQ-NCD. Self-reported adherence was high. Ongoing reassessment of patients' beliefs about the necessity of taking their post-ACS medications may be warranted to mitigate further decline in BMQ-NCD.

Contexte: L'adhésion à une pharmacothérapie préventive secondaire après la survenue d'un syndrome coronarien aigu (SCA) est généralement faible et associée à des manifestations cardiovasculaires récurrentes. Les croyances du patient au sujet de ses médicaments représentent un facteur prédictif majeur de la non-adhésion intentionnelle. Méthodologie: Cette étude observationnelle prospective avait pour objectif d'évaluer les croyances des patients au sujet des médicaments à prendre après la survenue d'un SCA, au moyen du questionnaire BMQ (Beliefs About Medicines), ainsi que l'adhésion thérapeutique, à l'aide de l'échelle de rapport sur l'adhésion aux médicaments MARS-5 (Medication Adherence Report Scale), à l'hôpital St. Paul de Vancouver, au Canada, de mai à décembre 2022. Les questionnaires BMQ et MARS-5 ont été administrés pendant l'hospitalisation, puis 4 semaines après le congé de l'hôpital. Les résultats comprenaient la différence du score BMQ-NCD (necessity-concerns differential ­ écart nécessité-inquiétudes), entre l'hospitalisation et le suivi à 4 semaines, et les facteurs associés au score BMQ-NCD. Résultats: Au total, 47 participants ont terminé l'étude, jusqu'au suivi à 4 semaines. L'âge moyen était de 64 ans, et 83 % des sujets étaient de sexe masculin. La plupart des sujets présentaient un SCA sans élévation du segment ST. Aucune variation du score BMQ-NCD (7,3 vs 6,6; p = 0,29) ou MARS-5 (22,8 vs 23,7; p = 0,06) n'a été observée entre le congé de l'hôpital et le suivi à 4 semaines; cependant, le score BMQ spécifique à la nécessité avait significativement diminué (20,3 vs 18.8; p = 0,002). Les origines ethniques sud-asiatiques et moyen-orientales étaient associées à des scores BMQ-NCD plus élevés que les origines européennes. L'occupation d'un emploi à temps partiel et le sexe masculin étaient associés à des scores BMQ-NCD inférieurs. Conclusions: Les participants entretenaient des croyances favorables envers leurs médicaments à prendre après la survenue d'un SCA, qui sont demeurées largement les mêmes entre l'hospitalisation et le suivi, 4 semaines après le congé de l'hôpital, à l'exception des croyances au sujet de la nécessité de prendre les médicaments. Les sujets d'origine européenne, ceux occupant un emploi à temps partiel et les sujets masculins ont eu les scores BMQ-NCD les plus faibles. L'adhésion thérapeutique autosignalée était élevée. Des réévaluations constantes des croyances des patients au sujet de la nécessité de prendre leurs médicaments après la survenue d'un SCA pourraient être justifiées afin d'éviter que les scores BMQ-NCD diminuent davantage.

Associations between individual hallucinogens and hallucinogen misuse among U.S. Adults who recently initiated hallucinogen use.

Hallucinogen dependence and abuse are DSM-IV diagnoses that are associated with significant morbidity, yet the specific hallucinogens that are most strongly linked to dependence and abuse are understudied. We used recent data from the National Survey on Drug Use and Health (2015-2020) and multivariable logistic regression to test the relationships that lifetime use of seven individual hallucinogens (MDMA/ecstasy, PCP, ketamine, psilocybin, LSD, peyote, and mescaline) shares with hallucinogen dependence and abuse among individuals who initiated hallucinogen use within the past two years (N = 5,252). We controlled for various demographic factors (sex, age, race/ethnicity, educational attainment, self-reported engagement in risky behavior, annual household income, marital status) and lifetime use of various substances. Lifetime PCP use was associated with increased odds of hallucinogen dependence or abuse (aOR [95% CI]: 6.27 [1.51, 26.0]). Additionally, PCP increased the odds of three main hallucinogen dependence and abuse criteria measures (aOR [95% CI]: 4.45 [1.11, 17.8], 5.58 [1.42, 22.0], and 7.01 [1.87, 26.3]). LSD conferred increased odds of two criteria (aOR: 2.33 [1.37, 3.98] and 2.53 [1.48, 4.33]), while ketamine and mescaline each conferred increased odds of one criterion (aOR: 2.12 [1.03, 4.39]; 5.39 [1.05, 27.7]). Future longitudinal studies and Bayesian statistical analyses can further assess the relationships between hallucinogens and disordered hallucinogen use.

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Examining associations between MDMA/ecstasy and classic psychedelic use and impairments in social functioning in a U.S. adult sample.

Impairment in social functioning is a common source of morbidity across many mental health disorders, yet there is a dearth of effective and easily implemented interventions to support social functioning. MDMA/ecstasy and classic psychedelics (psilocybin, LSD, peyote, mescaline) represent two potential treatments for impairments in social functioning, as evidence suggests these compounds may be supportive for alleviating social difficulties. Using a nationally representative sample of U.S. adults from the National Survey on Drug Use and Health (2015-2019) (N = 214,505), we used survey-weighted multivariable ordinal and logistic regression to examine the associations between lifetime use of the aforementioned compounds and impairments in social functioning in the past year. Lifetime MDMA/ecstasy use was associated with lowered odds of three of our four social impairment outcomes: difficulty dealing with strangers (aOR 0.92), difficulty participating in social activities (aOR 0.90), and being prevented from participating in social activities (aOR 0.84). Lifetime mescaline use was also associated with lowered odds of difficulty dealing with strangers (aOR 0.85). All other substances either shared no relationship with impairments in social functioning or conferred increased odds of our outcomes. Future experimental studies can assess whether these relationships are causal.

Comparison of a Fully Weight-Based Protocol with a Non-Weight-Based Dosage Titration Protocol for IV Unfractionated Heparin: A Before-and-After Study.

Background: Unfractionated heparin (UFH) is used for the prevention and treatment of arterial or venous thromboembolism. The dosage for IV infusion of UFH is generally based on the patient's weight, with adjustment to a specific target for activated partial thromboplastin time (aPTT). In May 2019, the UFH protocols at the study institution were changed from being fully weight-based (i.e., for both initial dosing and subsequent dosage titrations) to weight-based initial dosing and non-weight-based dosage titrations, but the relative effectiveness of these 2 approaches was not known. Objectives: The primary objective was to compare the effectiveness in achieving therapeutic aPTT with the fully weight-based and non-weight-based dosage titration protocols. The secondary objective was to compare the effectiveness of the non-weight-based dosage titration protocol with that of the previous fully weight-based one for patients with low-target aPTT. Methods: A single-centre, retrospective, observational before-and-after study was conducted for patients receiving therapeutic UFH for any indication. Patients in the "before" group (fully weight-based protocol) were treated from January 2015 to October 2016, and those in the "after" group (non-weight-based titration) from January to October 2020. Results: From a total of 1969 charts screened, 137 patients treated according to the fully weight-based protocols and 130 patients treated according to the non-weight-based titration protocols were included. In terms of the co-primary objective, the median number of dosage adjustments to achieve therapeutic anticoagulation was 1 in both groups (p = 0.48), and the proportion of patients with therapeutic anticoagulation at 24 h was similar (96.2% [125/130] with the non-weight-based titration protocols versus 99.3% [136/137] with the fully weight-based protocols; p = 0.09). Among patients treated according to the low-target UFH protocols, those with the non-weight-based titration protocol were less likely to have therapeutic anticoagulation at first measurement of aPTT than those with the fully weight-based protocol (37.9% [25/66] versus 44.6% [41/92], p = 0.033). Conclusions: This retrospective, observational, before-and-after study showed that the effectiveness of the non-weight-based dosage titration protocols in achieving therapeutic aPTT was similar to that of fully weight-based UFH protocols.

Contexte: L'héparine non fractionnée (HNF) est utilisée pour la prévention et le traitement de la thromboembolie artérielle ou veineuse. La posologie de la perfusion par IV d'HNF se base généralement sur le poids du patient, avec un ajustement à un objectif précis du temps moyen de céphaline activée (TCA). En mai 2019, les protocoles d'HNF de l'établissement à l'étude sont passés d'une approche entièrement basée sur le poids (à la fois pour la posologie initiale et les titrages posologiques ultérieurs) à une posologie initiale basée sur le poids, et à des titrages posologiques non basés sur le poids. Cependant, l'efficacité relative de ces 2 approches était inconnue. Objectifs: L'objectif principal de l'étude consistait à comparer dans quelle mesure les protocoles entièrement basés sur le poids et les protocoles de titrage non basés sur le poids étaient efficaces pour atteindre le TCA thérapeutique. L'objectif secondaire consistait quant à lui à comparer l'efficacité du protocole de titrage de dose non basé sur le poids au protocole précédent entièrement basé sur le poids chez les patients ayant une faible cible de TCA. Méthodes: Une étude monocentrique, rétrospective, observationnelle avant-après a été menée chez des patients recevant de l'HNF thérapeutique, toutes indications confondues. Les patients du groupe « Avant ¼ (protocole entièrement basé sur le poids) ont été traités de janvier 2015 à octobre 2016, et ceux du groupe « Après ¼ (protocole de titrage de dose non basé sur le poids) de janvier à octobre 2020. Résultats: À partir de 1969 dossiers examinés, 137 patients traités selon les protocoles entièrement basés sur le poids et 130 patients traités selon les protocoles d'ajustement posologique non basés sur le poids ont été inclus. En ce qui concerne l'objectif co-principal, le nombre médian d'ajustements posologiques pour obtenir une anticoagulation thérapeutique était de 1 dans les deux groupes (p = 0,48), et la part de patients ayant une anticoagulation thérapeutique à 24 h était similaire (96,2 % [125/130] avec les protocoles non basés sur le poids contre 99,3 % [136/137] avec ceux entièrement basés sur le poids [p = 0,09]). Parmi les patients traités selon les protocoles HNF à faible cible, ceux avec le protocole de titrage non basé sur le poids étaient moins susceptibles de connaître une anticoagulation thérapeutique à la première mesure du TCA que ceux avec le protocole entièrement basé sur le poids (37,9 % [25/66] contre 44,6 % [41/92], p = 0,033). Conclusions: Cette étude rétrospective et observationnelle avant-après a montré que l'efficacité des protocoles d'ajustement posologique non basés sur le poids pour obtenir un TCA thérapeutique était similaire à celle des protocoles d'HNF entièrement basés sur le poids.

Racial and ethnic disparities in polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a common endocrine disorder that impacts women worldwide. There are several racial and ethnic differences in PCOS phenotypes and in PCOS- associated metabolic dysfunction. In this review, we summarize the current literature on disparities in the diagnosis and outcomes associated with PCOS in the United States. Future studies are needed to address gaps in knowledge for racial and ethnic-specific differences in PCOS, and include a large number of non-White and/or Hispanic participants in PCOS studies.

Infertility and treatments used have minimal effects on first-trimester placental DNA methylation and gene expression.

OBJECTIVE: To determine whether deoxyribonucleic acid (DNA) methylation alterations exist in the first-trimester human placenta between conceptions using fertility treatments and those that do not and, if so, whether they are the result of underlying infertility or fertility treatments. We also assessed whether significant alterations led to changes in gene expression. DESIGN: We compared DNA methylation of the first-trimester placenta from singleton pregnancies that resulted in live births from unassisted, in vitro fertilization (IVF), and non-IVF fertility treatment (NIFT) conceptions using the Infinium MethylationEPIC BeadChip array. Significant CpG sites were compared with corresponding ribonucleic acid sequencing analysis in similar cohorts to determine whether methylation alterations lead to differences in gene expression. SETTING: Academic medical center. PATIENT(S): A total of 138 singleton pregnancies undergoing chorionic villus sampling resulting in a live birth were recruited for methylation analysis (56 unassisted, 38 NIFT, and 44 IVF conceptions). Ribonucleic acid-sequencing data consisted of 141 subjects (74 unassisted, 33 NIFT, and 34 IVF conceptions) of which 116 overlapped with the methylation cohort. INTERVENTION(S): In vitro fertilization-conceived pregnancy or pregnancy conceived via NIFT, such as ovulation induction and intrauterine insemination. MAIN OUTCOME MEASURE(S): Significant methylation changes at CpG sites after adjustment for multiple comparisons. The secondary outcome was gene expression changes of significant CpG sites. RESULT(S): Of the 741,145 probes analyzed in the placenta, few were significant at Bonferroni <0.05: 185 CpG sites (0.025%) significant in pregnancies conceived with the fertility treatments (NIFT + IVF) vs. unassisted conceptions; 28 in NIFT vs. unassisted; 195 in IVF vs. unassisted; and only 13 (0.0018%) in IVF vs. NIFT conceptions. Of all significant CpG sites combined, 10% (35) were located in genes with suggestive gene expression changes, but none were significant after adjustment for multiple comparisons (ribonucleic acid sequencing false discovery rate <0.05). None of the 13 differentially methylated probes in the IVF vs. NIFT placenta were located in genes with suggestive IVF vs. NIFT gene expression differences. CONCLUSION(S): Underlying infertility is the most significant contributor to the minimal differences in first-trimester placental methylation, and not the specific fertility treatment used, such as IVF.

Regional Variation in Hormonal and Metabolic Parameters of White and Black Women With PCOS in the United States.

CONTEXT: Ongoing research is needed to determine geo-epidemiologic differences of polycystic ovary syndrome (PCOS). OBJECTIVE: Determine hormonal and metabolic parameters of women with PCOS in 2 environments. METHODS: Prospective cohort study. SETTING: Tertiary-care based specialty clinics in Alabama and California. PATIENTS OR OTHER PARTICIPANTS: A total of 1610 women with PCOS by National Institutes of Health Criteria from 1987 to 2010. INTERVENTIONS: Interview, physical examination, laboratory studies. MAIN OUTCOMES MEASURES: Demographic data, menstrual cycle history, and hormonal and metabolic parameters were collected. Hirsutism was defined as modified Ferriman-Gallwey scores ≥4. Androgen values greater than laboratory reference ranges or >95th percentile of all values were considered elevated (hyperandrogenemia). Metabolic parameters included body mass index (BMI), waist-hip-ratio (WHR), glucose tolerance test, and homeostatic model assessment for insulin resistance (HOMA-IR) scores. RESULTS: Alabama women with PCOS were younger with a higher BMI. After adjustment for age and BMI, Alabama women with PCOS were more likely hirsute (adjusted odds ratio [aOR], 1.8; 95% CI, 1.4-2.4; P < 0.001), with elevated HOMA-IR scores (adjusted beta coefficient 3.6; 95% CI, 1.61-5.5; P < 0.001). California women with PCOS were more likely to have hyperandrogenemia (free testosterone aOR, 0.14; 95% CI, 0.11-0.18; P < 0.001; total testosterone aOR, 0.41; 95% CI, 0.33-0.51). Results were similar when stratified by White race. In Black women with PCOS, BMI and WHR did not differ between locations, yet differences in androgen profiles and metabolic dysfunction remained. CONCLUSION: Alabama women with PCOS, regardless of Black or White race, were more likely hirsute with metabolic dysfunction, whereas California women with PCOS were more likely to demonstrate hyperandrogenemia, highlighting potential environmental impacts on PCOS.

Ovarian volume as an independent marker for metabolic dysfunction in women with suspected androgen excess.

Objective: To determine whether ovarian volume (OV) alone is an independent marker for metabolic dysfunction in women with suspected androgen excess. Design: Retrospective cohort study. Setting: Tertiary academic reproductive endocrinology clinic. Patients: Women aged ≥21 years recruited/referred for symptoms related to androgen excess. Interventions: Transvaginal ovarian ultrasound, physical and medical evaluation, 2-hour 75-g oral glucose tolerance test (oGTT), and blood sampling. Main Outcome Measures: Prevalence of hyperandrogenism and metabolic dysfunction. Results: This study included 666 women, of whom 412 (61.9%) and 254 had OVs of >10 and ≤10 mL, respectively. An OV of >10 mL was associated with a higher prevalence of hirsutism (65.1% vs. 51.5%) than an OV of ≤10 mL. Polycystic ovary syndrome by the National Institutes of Health 1990 criteria was found in 67.3% and 51.4% of women with OVs of >10 and ≤10 mL, respectively. Metabolic parameters, including body mass index, waist circumference, and 1-hour insulin levels during the oGTT (odds ratio, 1.98; 95% confidence interval, 1.18-3.31), were significantly higher in women with an OV of >10 mL than in those with an OV of ≤10 mL. An OV of ≤10 mL had a 76.3% negative predictive value for hyperinsulinemia at 1 hour. Conclusions: In women with suspected androgen excess, an OV of >10 mL in at least 1 ovary is not associated with metabolic syndrome but is associated with younger age; an increased body mass index and waist circumference; a higher prevalence of hirsutism, oligoovulation, and polycystic ovary syndrome; and a higher 60-minute insulin level during the oGTT. Overall, an increased OV appears to be a good marker for hyperinsulinemia and hyperandrogenism in women suspected of having an androgen excess disorder.

Clinical and Pathological Characteristics and Outcomes Among Patients With Subcutaneous Panniculitis-like T-Cell Lymphoma and Related Adipotropic Lymphoproliferative Disorders.

Importance: There is a knowledge gap about subcutaneous panniculitis-like T-cell lymphoma (SPTCL) owing to its rarity and diagnostic difficulty, resulting in an absence of well-documented large case series published to date. Objective: To generate consensus knowledge by a joint multi-institutional review of SPTCL and related conditions. Design, Setting, and Participants: This retrospective clinical and pathological review included cases initially diagnosed as SPTCL at 6 large US academic centers. All cases were reviewed by a group of pathologists, dermatologists, and oncologists with expertise in cutaneous lymphomas. Through a process of group consensus applying defined clinical and pathological diagnostic criteria, the cohort was classified as (1) SPTCL or (2) adipotropic lymphoproliferative disorder (ALPD) for similar cases with incomplete histopathological criteria for SPTCL designation. Exposures: Cases of SPTCL diagnosed between 1998 and 2018. Main Outcomes and Measures: The main outcome was disease presentation and evolution, including response to therapy, disease progression, and development of hemophagocytic lymphohistiocytosis. Results: The cohort of 95 patients (median [range] age, 38 [2-81] years; female-to-male ratio, 2.7) included 75 cases of SPTCL and 20 cases of ALPD. The clinical presentation was similar for both groups with multiple (61 of 72 [85%]) or single (11 of 72 [15%]) tender nodules mostly involving extremities, occasionally resulting in lipoatrophy. Hemophagocytic lymphohistiocytosis (HLH) was only observed in SPTCL cases. With a mean follow-up of 56 months, 60 of 90 patients (67%) achieved complete remission with a median (range) of 3 (1-7) cumulative therapies. Relapse was common. None of the patients died of disease progression or HLH. Two patients with ALPD eventually progressed to SPTCL without associated systemic symptoms or HLH. Conclusions and Relevance: In this case series of patients initially diagnosed as having SPTCL, results showed no evidence of systemic tumoral progression beyond the adipose tissue. The SPTCL experience in this study confirmed an indolent course and favorable response to a variety of treatments ranging from immune modulation to chemotherapy followed by hematopoietic stem cell transplantation. Morbidity was primarily associated with HLH.

Sex differences in microRNA expression in first and third trimester human placenta†.

Maternal and fetal pregnancy outcomes related to placental function vary based on fetal sex, which may be due to sexually dimorphic epigenetic regulation of RNA expression. We identified sexually dimorphic miRNA expression throughout gestation in human placentae. Next-generation sequencing identified miRNA expression profiles in first and third trimester uncomplicated pregnancies using tissue obtained at chorionic villous sampling (n = 113) and parturition (n = 47). Sequencing analysis identified 986 expressed mature miRNAs from female and male placentae at first and third trimester (baseMean>10). Of these, 11 sexually dimorphic (FDR < 0.05) miRNAs were identified in the first and 4 in the third trimester, all upregulated in females, including miR-361-5p, significant in both trimesters. Sex-specific analyses across gestation identified 677 differentially expressed (DE) miRNAs at FDR < 0.05 and baseMean>10, with 508 DE miRNAs in common between female-specific and male-specific analysis (269 upregulated in first trimester, 239 upregulated in third trimester). Of those, miR-4483 had the highest fold changes across gestation. There were 62.5% more female exclusive differences with fold change>2 across gestation than male exclusive (52 miRNAs vs 32 miRNAs), indicating miRNA expression across human gestation is sexually dimorphic. Pathway enrichment analysis identified significant pathways that were differentially regulated in first and third trimester as well as across gestation. This work provides the normative sex dimorphic miRNA atlas in first and third trimester, as well as the sex-independent and sex-specific placenta miRNA atlas across gestation, which may be used to identify biomarkers of placental function and direct functional studies investigating placental sex differences.

The safety of high-dose dexmedetomidine after cardiac surgery: a historical cohort study.

PURPOSE: The off-label use of dexmedetomidine beyond the monograph-recommended maximum dose of 0.7 µg·kg-1·hr-1 is common in postoperative cardiac surgical units; however, limited data exist on the association of higher doses and adverse hemodynamic effects. We sought to compare the rate of hypotension or bradycardia in cardiac surgery patients receiving peak infusion doses below and above 0.7 µg·kg-1·hr-1 for any indication or duration. METHODS: In this historical cohort study, we reviewed all patients who received dexmedetomidine infusion after cardiac surgery between June 2013 and July 2017 at a single centre. Regardless of the duration of exposure at the peak infusion dose, patients were categorized into high- or standard-dose groups using 0.7 µg·kg-1·hr-1 as the cutoff value. We compared rates of the primary composite outcome of hypotension or bradycardia, and secondary outcomes (i.e., arrhythmia and hyperglycemia) between groups using the two-proportion z test. Exploratory regression models were fitted to adjust for potential confounders. RESULTS: The median [interquartile range (IQR)] peak infusion dose was 1.0 [1.0-1.4] µg·kg-1·hr-1 in the high-dose group (N = 121) and 0.5 [0.4-0.7] µg·kg-1·hr-1 in the standard-dose group (N = 124). The rates of the primary composite outcome were 73% and 65%, respectively (absolute risk difference, 8%; 95% confidence interval, -3 to 20; P = 0.17). There was no significant difference in primary or secondary outcomes between groups. CONCLUSION: There was a high overall rate of hypotension or bradycardia in patients receiving dexmedetomidine after cardiac surgery; infusion rates below or above 0.7 µg·kg-1·hr-1 had similar rates of adverse hemodynamic events.

RéSUMé: OBJECTIF: L'utilisation non conforme (off-label) de la dexmédétomidine au-delà de la dose maximale recommandée dans la monographie de 0,7 µg·kg−1·h−1 est fréquente dans les unités de chirurgie cardiaque postopératoire; cependant, il n'existe que peu de données sur l'association entre des doses plus élevées et des effets hémodynamiques indésirables. Nous avons cherché à comparer le taux d'hypotension ou de bradycardie chez les patients de chirurgie cardiaque recevant des doses de perfusion maximales inférieures ou supérieures à 0,7 µg·kg−1·h−1 pour toute indication ou durée. MéTHODE: Dans cette étude de cohorte historique, nous avons passé en revue tous les patients qui ont reçu une perfusion de dexmédétomidine après une chirurgie cardiaque entre juin 2013 et juillet 2017 dans un seul centre. Quelle que soit la durée de l'exposition à la dose de perfusion maximale, les patients ont été classés en groupes à dose élevée ou standard selon une valeur seuil de 0,7 µg·kg−1·h−1. Nous avons comparé les taux d'hypotension ou de bradycardie, notre critère d'évaluation principal composite, et les taux des critères d'évaluation secondaires (soit l'arythmie et l'hyperglycémie) entre les groupes à l'aide du test z à deux proportions. Des modèles de régression exploratoire ont été ajustés pour tenir compte des facteurs de confusion potentiels. RéSULTATS: La dose de perfusion maximale médiane [écart interquartile (ÉIQ)] était de 1,0 [1,0­1,4] µg·kg−1·h−1 dans le groupe à forte dose (n = 121) et de 0,5 [0,4­0,7] µg·kg−1·h−1 dans le groupe à dose standard (n = 124). Les taux pour le critère d'évaluation principal composite étaient de 73% et 65%, respectivement (différence de risque absolue, 8%; intervalle de confiance à 95%, -3 à 20; P = 0,17). Aucune différence intergroupe significative n'a été observée dans les critères d'évaluation primaires ou secondaires. CONCLUSION: Nous avons observé un taux global élevé d'hypotension ou de bradycardie chez les patients recevant de la dexmédétomidine après une chirurgie cardiaque; les taux de perfusion inférieurs ou supérieurs à 0,7 µg·kg−1·h−1 ont entraîné des taux similaires d'événements hémodynamiques indésirables.

Materials, surfaces, and interfacial phenomena in nanoplastics toxicology research.

In response to the growing worldwide plastic pollution problem, the field of nanoplastics research is attempting to determine the risk of exposure to nanoparticles amidst their ever-increasing presence in the environment. Since little is known about the attributes of environmental nanoplastics (concentration, composition, morphology, and size) due to fundamental limitations in detection and quantification of smaller plastic particles, researchers often improvise by engineering nanoplastic particles with various surface modifications as models for laboratory toxicological testing. Polystyrene and other commercially available or easily synthesized polymer materials functionalized with surfactants or fluorophores are typically used for these studies. How surfactants, additives, fluorophores, the addition of surface functional groups for conjugation, or other changes to surface attributes alter toxicological profiles remains unclear. Additionally, the limited polymers used in laboratory models do not mimic the vast range of polymer types comprising environmental pollutants. Nanomaterials are tricky materials to investigate due to their high surface area, high surface energies, and their propensity to interact with molecules, proteins, and biological probes. These unique properties can often invalidate common laboratory assays. Extreme care must be taken to ensure that results are not artefactual. We have gathered zeta potential values for various polystyrene nanoparticles with different functionalization, in different solvents, from the reported literature. We also discuss the effects of surface engineering and solvent properties on interparticle interactions, agglomeration, particle-protein interactions, corona formation, nano-bio interfaces, and contemplate how these parameters might confound results. Various toxicological exemplars are critically reviewed, and the relevance and shortfalls of the most popular models used in nanoplastics toxicity studies published in the current literature are considered.

Safety and Efficacy of Non-Vitamin K Oral Anticoagulant Use Early After Cardiac Surgery: A Systematic Review.

OBJECTIVE: To determine the safety and efficacy of non-vitamin K oral anticoagulants (NOACs) initiated early after cardiac surgery. DATA SOURCES: Cochrane Central Register of Controlled Trials, EMBASE, and MEDLINE (database inception to January 20, 2021), www.clinicaltrials.gov, www.who.int/ictrp/search/en/, NOAC trial registries, and bibliographies of relevant guidelines and other reviews were used. STUDY SELECTION AND DATA EXTRACTION: Observational studies and randomized controlled trials (RCTs) that initiated NOACs within the index hospitalization and that reported bleeding for the primary outcome were included. DATA SYNTHESIS: A total of 6 cohort studies, 1 RCT, and 3 ongoing RCTs were included. Most studies were single-centered, limited to postoperative atrial fibrillation after coronary artery bypass grafting, and with 30-day follow-up; few studies included patients with isolated bioprosthetic valve replacement or valve repair. Bleeding risk varied (0%-28.6%), and all but one study showed no significantly higher risk with NOAC compared with warfarin. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: Overall, NOACs were used in 26% to 37.5% of patients early after cardiac surgery. Starting a NOAC on postoperative day 4 appeared to have similar bleeding rates compared with warfarin, but clinical application is limited by heterogeneity of outcome definitions, confounding, and bias. Compared with warfarin, NOACs may have similar thromboembolism risk, reduced length of stay, and cost. CONCLUSIONS: There is limited evidence to guide NOAC use early after cardiac surgery. Three ongoing randomized trials will add to the literature and provide guidance for clinicians on whether, in whom, when, and how to use NOACs safely early after cardiac surgery.