Thromboembolic Rates Are Similar Between Intensive Care Unit and Nonintensive Care Unit Hospitalized Patients With Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2): A Retrospective Cohort Study.

High rates of thromboembolic events have been described in intensive care unit (ICU) patients. Data regarding thromboembolic events in all hospitalized patients has been less frequently reported, raising concerns that thromboembolic events in non-ICU may be underrecognized. In addition, optimal anticoagulation type and dose is still unsettled at this time. This is a retrospective cohort study of 159 hospitalized patients with coronavirus disease 2019 (COVID-19) pneumonia during a 9-month period to determine an association between the frequency of thromboembolic rates and hospitalized patients with COVID-19. Secondary outcomes sought to investigate association of thromboembolic events with relation to place of admission, risk factors, anticoagulation, mortality, hospital length of stay, and discharge disposition. Among the cohort of 159 hospitalized patients who met criteria, 16 (10%) were diagnosed with a thromboembolic event. There were a total of 18 thromboembolic events with 12 venous and 6 arterial. Admission to the ICU was not associated with a higher frequency of thromboembolic events compared with non-ICU patients (37.5% vs 62.5%), p = .71. Patients with a thromboembolic event had a significantly higher mortality compared with those with no thromboembolic event (37.5% vs 13.3%), p = .012. Patients hospitalized with COVID-19 have increased rates of thromboembolic events, both venous and arterial, which contribute to a significant increase in mortality. However, the frequency of thromboembolism in patients admitted to the ICU was similar to events in non-ICU patients. We hope to increase awareness of the increased risk of hypercoagulability in all hospitalized patients with COVID-19 including non-ICU patients.

A Case-Based Review of Systemic Mastocytosis and Its Cutaneous Manifestations.

Mastocytosis represents an uncommon spectrum of disorders where mast cells proliferate and accumulate in different organs and tissues throughout the body, most frequently affecting the skin. Here we present a case of systemic mastocytosis and review the manifestations of cutaneous and systemic mastocytosis to raise awareness and try to reduce the typical delay in diagnosis.

Comparison of Graft Acquisition and Early Direct Charges of Haploidentical Related Donor Transplantation versus Umbilical Cord Blood Transplantation.

Alternative donor allogeneic hematopoietic cell transplants (HCTs), such as double umbilical cord blood transplants (dUCBT) and haploidentical related donor transplants (haplo-HCT), have been shown to be safe and effective in adult patients who do not have an HLA-identical sibling or unrelated donor available. Most transplant centers have committed to 1 of the 2 alternative donor sources, even with a lack of published randomized data directly comparing outcomes and comparative data on the cost-effectiveness of dUCBT versus haplo-HCT. We conducted a retrospective study to evaluate and compare the early costs and charges of haplo-HCT and dUCBT in the first 100 days at 2 US transplant centers. Forty-nine recipients of haplo-HCT (at 1 center) and 37 with dUCBT (at another center) were included in the analysis. We compared graft acquisition, inpatient/outpatient, and total charges in the first 100 days. The results of the analysis showed a significantly lower cost of graft acquisition and lower total charges (for 100-day HCT survivors) in favor of haplo-HCT. Importantly, to control for the obvious shortcomings of comparing costs at 2 different transplant centers, adjustments were made based on the current (2018) local wage index and inflation rate. In the absence of further guidance from a prospective study, the cost analysis in this study suggests that haplo-HCT may result in early cost savings over dUCBT and may be preferred by transplant centers and for patients with more limited resources.

Incorporating newer agents in the treatment of acute myeloid leukemia.

Prognosis for patients with AML remains dismal. Despite multiple clinical trials across several decades, little improvement for the therapy of non-APL AML was noted. However, over the last couple of years, several new therapies have demonstrated efficacy in the therapy of patients with AML. Several of those have been approved by the FDA for AML therapy. These include CPX-351, midostaurin, gemtuzumab ozogamicin, enasidenib and ivosidenib. Our goal in this review is to summarize currently available data on these new therapies and discuss the rapidly evolving treatment landscape of AML.

Amebic Encephalitis in a Patient with Chronic Lymphocytic Leukemia on Ibrutinib Therapy.

Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in Western countries. A common first-line therapy offered to qualifying patients includes ibrutinib, an oral covalent inhibitor of Bruton's tyrosine kinase. Treatment of CLL with ibrutinib therapy is generally well tolerated; however, serious opportunistic infections are being reported in patients treated with ibrutinib. In this report, we present a patient with CLL on ibrutinib therapy who developed rapidly declining neurological status concerning for the central nervous system (CNS) process related to his immunocompromised status. Despite multiple testing modalities, no evidence was found to explain the acute changes the patient was experiencing, and he had no improvement with common antimicrobial coverage. The patient ultimately expired, and autopsy of the brain revealed granulomatous amebic encephalitis due to opportunistic infection by Acanthamoeba species. As evidenced by this case, ibrutinib therapy, despite being generally well tolerated, has the potential to predispose patients to opportunistic infections like amebic encephalitis. Amebic encephalitis is a highly lethal CNS infection, and it is important for clinicians to recognize early on the potential for infection in patients on ibrutinib therapy presenting with CNS symptoms.

Peripheral Blood Grafts for T Cell-Replete Haploidentical Transplantation Increase the Incidence and Severity of Cytokine Release Syndrome.

T cell-replete post-transplant cyclophosphamide (PTCy)-based protocols have led to increasing use of haploidentical allogeneic hematopoietic cell transplantation (haploHCT). With this approach, bidirectional alloreactivity causing nonengraftment or severe graft-versus-host disease (GVHD) is no a longer major barrier to haploHCT. PTCy eliminates alloreactive lymphocytes but spares CD34+ stem cells and regulatory T lymphocytes, resulting in reliable hematopoietic recovery with relatively low incidence of GVHD. The immediate post-haploHCT course, usually before PTCy administration, is often complicated by cytokine release syndrome (CRS). The predictors of CRS and its effect on outcomes post-transplant have not been fully ascertained. We analyzed the outcomes of 66 patients who received haploHCT at our institution. Using published CRS criteria we identified 48 patients who developed CRS. In multivariate analysis peripheral blood grafts were significantly associated with grade ≥ 2 CRS, compared with bone marrow. Grade ≥ 2 CRS (compared with grade < 2) was not associated with differences in overall survival or nonrelapse mortality. Severe CRS was associated with a statistically nonsignificant trend toward higher incidences of grades III to IV acute GVHD, especially in the context of peripheral blood grafts. CRS is a common complication after T cell-replete peripheral blood haploHCT, but post-transplant survival outcomes may not be affected in those with severe CRS.

Efficacy of High-Dose Therapy and Autologous Hematopoietic Cell Transplantation in Gray Zone Lymphoma: A US Multicenter Collaborative Study.

High-dose therapy (HDT) and autologous hematopoietic cell transplantation (auto-HCT) has been anecdotally prescribed in gray zone lymphoma (GZL), showing encouraging efficacy. We conducted a multicenter retrospective study aimed at assessing outcomes after auto-HCT in 32 patients with GZL treated at 9 transplantation centers in the United States. The median age of patients at transplantation was 38 years (range, 18 to 70 years), and the majority were male (n = 21; 66%). The median number of lines of therapy before transplantation was 2 (range, 1 to 4). BEAM was the most commonly prescribed regimen (n = 23; 72%). The median duration of follow-up for surviving patients was 34 months (range, 1 to 106 months). Median overall survival (OS) was not reached. The 3-year progression-free survival (PFS) and OS for all patients were 69% and 78%, respectively. Three-year PFS and OS were 100% for patients who received only 1 line of therapy before auto-HCT versus 65% (PFS, P = .25) and 75% (OS, P = .39) for those receiving >1 line. The cumulative incidence of relapse/progression was 4% at 1 year post-transplantation and 31% at 3 years post-transplantation. The 3-year nonrelapse mortality was 0%. These findings suggest that HDT and auto-HCT is an effective treatment in patients with GZL. Our findings ideally require confirmation in a larger cohort of patients, preferably in the setting of large prospective multicenter randomized controlled trials. However, we acknowledge that such studies could be difficult to conduct in patients with GZL owing to the disease's rarity. Alternatively, a multicenter prospective study that includes tissue banking and a data registry is warranted to help better understand the biology and natural history of the disease.

Haematopoietic cell transplantation for blastic plasmacytoid dendritic cell neoplasm: a North American multicentre collaborative study.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is incurable with conventional therapies. Limited retrospective data have shown durable remissions after haematopoietic cell transplantation (HCT) [allogeneic (allo) or autologous (auto)]. We conducted a multicentre retrospective study in BPDCN patients treated with allo-HCT and auto-HCT at 8 centres in the United States and Canada. Primary endpoint was overall survival (OS). The population consisted of 45 consecutive patients who received an allo-HCT (n = 37) or an auto-HCT (n = 8) regardless of age, pre-transplant therapies, or remission status at transplantation. Allo-HCT recipients were younger (50 (14-74) vs. 67 (45-72) years, P = 0·01) and had 1-year and 3-year OS of 68% [95% confidence interval (CI) = 49-81%] and 58% (95% CI = 38-75%), respectively. Allo-HCT in first complete remission (CR1) yielded superior 3-year OS (versus not in CR1) [74% (95% CI = 48-89%) vs. 0, P < 0·0001]. Allo-HCT outcomes were not impacted by regimen intensity [3-year OS for myeloablative conditioning = 61% (95% CI = 28-83%) vs. reduced-intensity conditioning = 55% (95% CI = 28-76%)]. One-year OS for auto-HCT recipients was 11% (95% CI = 8-50%). These results demonstrate efficacy of allo-HCT in BPDCN, especially in patients in CR1. Pertaining to auto-HCT, our results suggest lack of efficacy against BPDCN, but this observation is limited by the small sample size. Larger prospective studies are needed to better define the role of HCT in BPDCN.

Cost Implications for Subsequent Perinatal Outcomes After IVF Stratified by Number of Embryos Transferred: A Five Year Analysis of Vermont Data.

BACKGROUND: In states in the USA without in vitro fertilzation coverage (IVF) insurance coverage, more embryos are transferred per cycle leading to higher risks of multi-fetal pregnancies and adverse pregnancy outcomes. OBJECTIVE: To determine frequency and cost of selected adverse perinatal complications based on number of embryos transferred during IVF, and calculate incremental cost per IVF live birth. METHODS: Medical records of patients who conceived with IVF (n = 116) and delivered at >20 weeks gestational age between 2007 and 2011 were evaluated. Gestational age at delivery, low birth weight (LBW) term births, and delivery mode were tabulated. Healthcare costs per cohort, extrapolated costs assuming 100 patients per cohort, and incremental costs per infant delivered were calculated. RESULTS: The highest prematurity and cesarean section rates were recorded after double embryo transfers (DET), while the lowest rates were found in single embryo transfers (SET). Premature singleton deliveries increased directly with number of transferred embryos [6.3 % (SET), 9.1 % (DET) and 10.0 % for ≥3 embryos transferred]. This trend was also noted for rate of cesarean delivery [26.7 % (SET), 36.6 % (DET), and 47.1 % for ≥3 embryos transferred]. The proportion of LBW infants among deliveries after DET and for ≥3 embryos transferred was 3.9 and 9.1 %, respectively. Extrapolated costs per cohort were US$718,616, US$1,713,470 and US$1,227,396 for SET, DET, and ≥3 embryos transferred, respectively. CONCLUSION: Attempting to improve IVF pregnancy rates by permitting multiple embryo transfers results in sharply increased rates of multiple gestation and preterm delivery. This practice yields a greater frequency of adverse perinatal outcomes and substantially increased healthcare spending. Better efforts to encourage SET are necessary to normalize healthcare expenditures considering the frequency of very high cost sequela associated with IVF where multiple embryo transfers occur.

Regulators of ovarian preantral follicle development.

Preantral follicle development has become an increasingly recognized area of study in the last two decades. Factors that regulate the growth survival and differentiation of these small, yet complex structures have been identified. The field of fertility preservation and a need for increased numbers of mature oocytes for stem cell research revealed how little we knew of how follicles got from the primordial stage to the antral stage with a healthy and competent oocyte inside. This work discusses the role of gonadotropins in regulating preantral follicles and also the role of the TGF-ß family members and their associated Smad signaling molecules in preantral follicle development. Preantral follicle development is a necessary step to fertility in females and further understanding of this process is essential for progress in both infertility care and the enlarging field of in vitro folliculogenesis.

Christ Siemens Touraine syndrome: Two case reports and felicitous approaches to prosthetic management.

Ectodermal dysplasia is a heterogeneous group of inherited disorders, which exhibit a classic triad of hypohydrosis, hypotrichosis, and hypodontia. Hypohidrotic or anhidrotic ectodermal dysplasia or Christ Siemens Touraine syndrome is the most common condition among ectodermal dysplasia patients. This is a case report on two Christ Siemens Touraine syndrome cases and two different approaches to prosthetic management.

Implantation failure in female Kiss1-/- mice is independent of their hypogonadic state and can be partially rescued by leukemia inhibitory factor.

The hypothalamic kisspeptin signaling system is a major positive regulator of the reproductive neuroendocrine axis, and loss of Kiss1 in the mouse results in infertility, a condition generally attributed to its hypogonadotropic hypogonadism. We demonstrate that in Kiss1(-/-) female mice, acute replacement of gonadotropins and estradiol restores ovulation, mating, and fertilization; however, these mice are still unable to achieve pregnancy because embryos fail to implant. Progesterone treatment did not overcome this defect. Kiss1(+/-) embryos transferred to a wild-type female mouse can successfully implant, demonstrating the defect is due to maternal factors. Kisspeptin and its receptor are expressed in the mouse uterus, and we suggest that it is the absence of uterine kisspeptin signaling that underlies the implantation failure. This absence, however, does not prevent the closure of the uterine implantation chamber, proper alignment of the embryo, and the ability of the uterus to undergo decidualization. Instead, the loss of Kiss1 expression specifically disrupts embryo attachment to the uterus. We observed that on the day of implantation, leukemia inhibitory factor (Lif), a cytokine that is absolutely required for implantation in mice, is weakly expressed in Kiss1(-/-) uterine glands and that the administration of exogenous Lif to hormone-primed Kiss1(-/-) female mice is sufficient to partially rescue implantation. Taken together, our study reveals that uterine kisspeptin signaling regulates glandular Lif levels, thereby identifying a novel and critical role for kisspeptin in regulating embryo implantation in the mouse. This study provides compelling reasons to explore this role in other species, particularly livestock and humans.

Influenza, immune system, and pregnancy.

Influenza is a major health problem worldwide. Both seasonal influenza and pandemics take a major toll on the health and economy of our country. The present review focuses on the virology and complex immunology of this RNA virus in general and in relation to pregnancy. The goal is to attempt to explain the increased morbidity and mortality seen in infection during pregnancy. We discuss elements of innate and adaptive immunity as well as placental cellular responses to infection. In addition, we delineate findings in animal models as well as human disease. Increased knowledge of maternal and fetal immunologic responses to influenza is needed. However, enhanced understanding of nonimmune, pregnancy-specific factors influencing direct interaction of the virus with host cells is also important for the development of more effective prevention and treatment options in the future.

Generalized disturbance of DNA methylation in the uterine decidua in the CBA/J x DBA/2 mouse model of pregnancy failure.

Nonchromosomal pregnancy failure is a common but poorly understood phenomenon. Because recent data have suggested that epigenetic abnormalities such as abnormal placental DNA methylation may play a role in human pregnancy failure, we undertook experiments to test whether decidual and/or placental DNA methylation abnormalities are present in a mouse model of pregnancy failure. A large number of studies have shown that crosses between CBA/J female mice and DBA/2 males result in pregnancies with a high rate of failure/resorption, whereas other crosses with CBA/J females produce normal pregnancies. Although the CBA/J × DBA/2 mouse has frequently been used as a model for miscarriage, a detailed explanation for the pregnancy failure phenotype is lacking. We performed timed matings between CBA/J female and DBA/2 male mice as well as between DBA/2 female and CBA/J male mice. Decidual caps were isolated at Embryonic Day (E) 9.5 from both crosses, and a microarray-based method was used to comparatively assess genomic methylation at approximately 16,000 loci on mouse chromosome 7. In comparison with decidual caps from DBA/2 × CBA/J pregnancies, CBA/J × DBA/2 decidual caps were characterized by widely and apparently randomly disturbed methylation. In another set of analogous experiments, genomic methylation of placental DNA from E8.5 pregnancies was assessed using the same microarray-based method. This analysis revealed that in contrast to the decidua, placental DNA methylation from CBA/J × DBA/2 pregnancies was indistinguishable from that of normal controls. We conclude that abnormal DNA methylation in the uterine decidua likely plays a role in the CBA/J × DBA/2 model of pregnancy failure. To our knowledge, these experiments are the first to demonstrate that epigenetic abnormalities of the decidua are associated with pregnancy failure, and they set the stage for future efforts to understand the role of DNA methylation at the maternal-fetal interface.

A Time-motion Comparison of Itemized Treatment Costs in First and Second In Vitro Fertilization Attempts: A United Kingdom Fertility Centre Experience.

Objective: To assess the difference in cost between initial and second in vitro fertilization (IVF) cycles in the United Kingdom. Methods: This prospective time-motion analysis captured data on average time spent on 31 representative components of the IVF sequence as provided by clinical team members in seven categories. Audits of consumables and observations on personnel costs were made from total of 120 fertility patients undergoing initial or second IVF cycles (n=736) between 1 January 2002 and 31 December 2002 at a UK assisted fertility unit. Results: Patients spent an average of 16.71±4.3 hrs with staff during an initial IVF cycle, resulting in direct personnel costs of £577.05±151.01. When consumables were included, each initial cycle cost the clinic approximately £2246.57±151.01. For second IVF cycles, patients spent significantly less time with staff compared to their first IVF cycle (6.94±2.44 hrs; p<0.05), corresponding to £257.53±90.77 in personnel cost. Conclusions: This is the first economic appraisal of the IVF treatment sequence in the UK using a timemotion analysis model. Our study found that when combined with consumables, total institutional costs for second IVF cycles were significantly reduced when compared to initial cycles (£1813.12±90.77; p<0.05). Aggregating data from all IVF cycles performed within the fertility centre during the study interval, initial cycles were found to be front-loaded, resulting in £252,420 more in institutional costs as compared with subsequent IVF cycles. While these observations were registered in 2003, an inflation adjustment using recent European Commission Eurostat data for healthcare finds the difference between initial and subsequent fresh IVF cycles in present currency to be approximately £579.14 per cycle. Time-motion analysis can identify episodes of care that can be streamlined to improve outcomes and reduce cost.

Impact of experimental diabetes on the maternal uterine vascular remodeling during rat pregnancy.

Normal pregnancy is associated with an increase in uteroplacental blood flow in part due to growth and remodeling of the maternal uterine vasculature. In this study, we characterized the effect of diabetic pregnancy on vascular growth of the maternal uterine vasculature and on the passive mechanical properties of the uterine resistance arteries. Diabetes was induced in pregnant rats by injection of streptozotocin and confirmed by development of hyperglycemia. Fetuses of diabetic rats were significantly smaller and placentas larger compared to controls. Pregnancy-induced axial elongation of the mesometrial uterine vasculature was not altered by diabetes. Vascular wall thickness was unchanged between groups. Wall distensibility was increased and the rate constant of an exponential function fitted to stress-strain curve was significantly reduced demonstrating decreased wall stiffness in diabetic uterine radial arteries compared to controls. We conclude that experimental diabetes in rat pregnancy does not compromise the growth of maternal uterine vasculature but alters passive mechanical properties of the uterine radial arteries.