The effectiveness of cervical mucus electrical impedance compared to basal body temperature to determine fertility window.

BACKGROUND: Serial serum hormone measurements and transvaginal ultrasound are reliable measures to predict ovulation. These measures are inconvenient and expensive therefore, basal body temperature charting (BBT) and urine ovulation predictor kits (OPK) for luteinizing hormone are often used to determine the 6-day fertile window. However, BBT does not clearly change until 1-2 days after ovulation. Additionally, while OPK can indicate positivity prior to ovulation, false readings are common. A novel alternative approach involves measuring electrolyte trends in cervical mucus using electrical impedance spectroscopy. Cervical mucus electrolyte measurements are associated with hormone level changes during the menstrual cycle. The purpose of this study was to compare the effectiveness of cervical mucus electrical impedance and basal body temperature. We sought to determine if cervical mucus electrolyte measurements provided improved detection of the ovulation day and therefore, improve fertility timing for women. METHODS: 14 healthy women between 18 and 44 years of age with normal menstrual cycles were enrolled in the Observational Study. Participants measured BBT and cervical mucus electrical impedance daily for 3 menstrual cycles using Kegg (Lady Technologies Inc. San Francisco, California, USA). Ovulation date for each cycle was confirmed by measuring hormone levels in urine and serum, and by vaginal ultrasound. RESULTS: Electrical impedance was significantly different between the follicular phase versus ovulatory date (p = 0.007) and between the luteal phase versus the ovulatory date (p = 0.007). A significant difference in the rate of change of cervical impedance measurements in the pre-ovulatory follicular phase was found compared to BBT (p = 0.0225). The sensitivity (+ 7.14%), specificity (+ 20.35%), and accuracy (+ 17.59) to determine the 1-day fertility window was significantly higher using cervical mucus impedance compared to BBT. CONCLUSIONS: BBT is considered unreliable for evaluating ovulatory function. Cervical mucus electrical impedance offers a novel measure of electrolyte changes associated with hormone levels. We report that pre-ovulatory electrical impedance patterns demonstrated higher sensitivity, specificity, and accuracy for determining the fertility window when compared to BBT. These findings suggest that changes in electrical impedance may provide an accurate method for predicting ovulation and for measuring ovulatory function.

FGL2 promotes tumour growth and attenuates infiltration of activated immune cells in melanoma and ovarian cancer models.

The tumour microenvironment is infiltrated by immunosuppressive cells, such as regulatory T cells (Tregs), which contribute to tumour escape and impede immunotherapy outcomes. Soluble fibrinogen-like protein 2 (sFGL2), a Treg effector protein, inhibits immune cell populations, via receptors FcγRIIB and FcγRIII, leading to downregulation of CD86 in antigen presenting cells and limiting T cell activation. Increased FGL2 expression is associated with tumour progression and poor survival in several different cancers, such as glioblastoma multiforme, lung, renal, liver, colorectal, and prostate cancer. Querying scRNA-seq human cancer data shows FGL2 is produced by cells in the tumour microenvironment (TME), particularly monocytes and macrophages as well as T cells and dendritic cells (DCs), while cancer cells have minimal expression of FGL2. We studied the role of FGL2 exclusively produced by cells in the TME, by leveraging Fgl2 knockout mice. We tested two murine models of cancer in which the role of FGL2 has not been previously studied: epithelial ovarian cancer and melanoma. We show that absence of FGL2 leads to a more activated TME, including activated DCs (CD86+, CD40+) and T cells (CD25+, TIGIT+), as well as demonstrating for the first time that the absence of FGL2 leads to more activated natural killer cells (DNAM-1+, NKG2D+) in the TME. Furthermore, the absence of FGL2 leads to prolonged survival in the B16F10 melanoma model, while the absence of FGL2 synergizes with oncolytic virus to prolong survival in the ID8-p53-/-Brca2-/- ovarian cancer model. In conclusion, targeting FGL2 is a promising cancer treatment strategy alone and in combination immunotherapies.

A Qualitative Study on the Effects of the COVID-19 Pandemic on Solid Organ Transplantation.

Introduction: Solid organ transplantation is a lifesaving intervention requiring extensive coordination and communication for timely and safe care. The COVID-19 pandemic posed unique challenges to the safety and management of solid organ transplantation. This descriptive qualitative study aimed to understand how hospital stakeholders were affected by and responded to the COVID-19 pandemic to contribute toward improved healthcare delivery responses and strategies during times of systemic strain on the healthcare system. Methods: One-hour-long semistructured interviews were performed in 3 cohorts: healthcare professionals (N = 6), administrative staff (N = 6), and recipients (N = 4). Interviews were analyzed using conventional thematic content analysis. Thematic saturation was reached within each cohort. Findings: Twelve codes and 6 major themes were identified including the Impact on Clinical Practice, Virtual Healthcare Delivery, Communication, Research, Education and Training, Mental Health and Future Pandemic Planning. Reflecting on these codes and major themes, 4 recommendations were developed (Anticipation and Preparation, Maximizing Existing Resources and Networks, Standardization and the Virtual Environment and Caring for the Staff) to guide transplant programs to optimize healthcare pathways while enhancing the best practices during future pandemics. Conclusion: Transplant programs will benefit from anticipation and preparation procedures using ramping-down strategies, resource planning, and interprofessional collaboration while maximizing existing resources and networks. In parallel, transplant programs should standardize virtual practices and platforms for clinical and educational purposes while maintaining an open culture of mental health discussion and integrating strategies to support staff's mental health.

Congenic hematopoietic stem cell transplantation promotes survival of heart allografts in murine models of acute and chronic rejection.

The ability to induce tolerance would be a major advance in the field of solid organ transplantation. Here, we investigated whether autologous (congenic) hematopoietic stem cell transplantation (HSCT) could promote tolerance to heart allografts in mice. In an acute rejection model, fully MHC-mismatched BALB/c hearts were heterotopically transplanted into C57BL/6 (CD45.2) mice. One week later, recipient mice were lethally irradiated and reconstituted with congenic B6 CD45.1 Lin-Sca1+ckit+ cells. Recipient mice received a 14-day course of rapamycin both to prevent rejection and to expand regulatory T cells (Tregs). Heart allografts in both untreated and rapamycin-treated recipients that did not undergo HSCT were rejected within 33 days (median survival time = 8 days for untreated recipients, median survival time = 32 days for rapamycin-treated recipients), whereas allografts in HSCT-treated recipients had a median survival time of 55 days (P < 0.001 vs. both untreated and rapamycin-treated recipients). Enhanced allograft survival following HSCT was associated with increased intragraft Foxp3+ Tregs, reduced intragraft B cells, and reduced serum donor-specific antibodies. In a chronic rejection model, Bm12 hearts were transplanted into C57BL/6 (CD45.2) mice, and congenic HSCT was performed two weeks following heart transplantation. HSCT led to enhanced survival of allografts (median survival time = 70 days vs. median survival time = 28 days in untreated recipients, P < 0.01). Increased allograft survival post-HSCT was associated with prevention of autoantibody development and absence of vasculopathy. These data support the concept that autologous HSCT can promote immune tolerance in the setting of allotransplantation. Further studies to optimize HSCT protocols should be performed before this procedure is adopted clinically.

Antibody dependent disease enhancement (ADE) after COVID-19 vaccination and beta glucans as a safer strategy in management.

A potential risk associated with vaccines for COVID-19 is antibody-dependent disease enhancement (ADE) in which vaccine induced antibody mediated immune responses may lead to enhanced SARS CoV- 2 acquisition or increased disease severity. Though ADE has not been clinically demonstrated with any of the COVID-19 vaccines so far, when neutralizing antibodies are suboptimal, the severity of COVID-19 has been reported to be greater. ADE is presumed to occur via abnormal macrophages induced by the vaccine based immune response by antibody-mediated virus uptake into Fc gamma receptor IIa (FcγRIIa) or by the formation of Fc-mediated excessive antibody effector functions. Beta-glucans which are naturally occurring polysaccharides known for unique immunomodulation by capability to interact with macrophages, eliciting a specific beneficial immune-response and enhancing all arms of the immune system, importantly without over-activation are suggested as safer nutritional supplement-based vaccine adjuvants for COVID-19.

Complete Cycle Mapping Using a Quantitative At-Home Hormone Monitoring System in Prediction of Fertile Days, Confirmation of Ovulation, and Screening for Ovulation Issues Preventing Conception.

Background and Objectives: To achieve pregnancy, it is highly beneficial to identify the time of ovulation as well as the greater period of fertile days during which sperm may survive leading up to ovulation. Confirming successful ovulation is also critical to accurately diagnose ovulatory disorders. Ovulation predictor kits, fertility monitors, and tracking apps are all available to assist with detecting ovulation, but often fall short. They may not detect the full fertile window, provide accurate or real-time information, or are simply expensive and impractical. Finally, few over-the-counter products provide information to women about their ovarian reserve and future fertility. Therefore, there is a need for an easy, over-the-counter, at-home quantitative hormone monitoring system that assesses ovarian reserve, predicts the entire fertile window, and can screen for ovulatory disorders. Materials and Methods: Proov Complete is a four-in-one at-home multihormone testing system that utilizes lateral flow assay test strips paired with the free Proov Insight App to guide testing of four hormones-FSH, E1G, LH, and PdG-across the woman's cycle. In a pilot study, 40 women (including 16 with a fertility-related diagnosis or using fertility treatments) used Complete for one cycle. Results: Here, we demonstrate that Proov Complete can accurately and sensitively predict ovarian reserve, detect up to 6 fertile days and confirm if ovulation was successful, in one easy-to-use kit. Ovulation was confirmed in 38 cycles with a detectable PdG rise. An average of 5.3 fertile days (from E1G rise to PdG rise) were detected, with an average of 2.7 days prior to LH surge. Ovulation was confirmed via PdG rise an average of 2.6 days following the LH surge. While 38/40 women had a PdG rise, only 22 had a sustained PdG level above 5 µg/mL throughout the critical implantation window, indicating ovulatory dysfunction in 16 women. Conclusions: Proov Complete can detect the entire fertile window of up to 6 fertile days and confirm ovulation, while also providing information on ovarian reserve and guidance to clinicians and patients.

SARS-CoV-2 mitochondriopathy in COVID-19 pneumonia exacerbates hypoxemia.

RATIONALE: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19 pneumonia. We hypothesize that SARS-CoV-2 causes alveolar injury and hypoxemia by damaging mitochondria in airway epithelial cells (AEC) and pulmonary artery smooth muscle cells (PASMC), triggering apoptosis and bioenergetic impairment, and impairing hypoxic pulmonary vasoconstriction (HPV), respectively. OBJECTIVES: We examined the effects of: A) human betacoronaviruses, SARS-CoV-2 and HCoV-OC43, and individual SARS-CoV-2 proteins on apoptosis, mitochondrial fission, and bioenergetics in AEC; and B) SARS-CoV-2 proteins and mouse hepatitis virus (MHV-1) infection on HPV. METHODS: We used transcriptomic data to identify temporal changes in mitochondrial-relevant gene ontology (GO) pathways post-SARS-CoV-2 infection. We also transduced AECs with SARS-CoV-2 proteins (M, Nsp7 or Nsp9) and determined effects on mitochondrial permeability transition pore (mPTP) activity, relative membrane potential, apoptosis, mitochondrial fission, and oxygen consumption rates (OCR). In human PASMC, we assessed the effects of SARS-CoV-2 proteins on hypoxic increases in cytosolic calcium, an HPV proxy. In MHV-1 pneumonia, we assessed HPV via cardiac catheterization and apoptosis using the TUNEL assay. RESULTS: SARS-CoV-2 regulated mitochondrial apoptosis, mitochondrial membrane permeabilization and electron transport chain (ETC) GO pathways within 2 hours of infection. SARS-CoV-2 downregulated ETC Complex I and ATP synthase genes, and upregulated apoptosis-inducing genes. SARS-CoV-2 and HCoV-OC43 upregulated and activated dynamin-related protein 1 (Drp1) and increased mitochondrial fission. SARS-CoV-2 and transduced SARS-CoV-2 proteins increased apoptosis inducing factor (AIF) expression and activated caspase 7, resulting in apoptosis. Coronaviruses also reduced OCR, decreased ETC Complex I activity and lowered ATP levels in AEC. M protein transduction also increased mPTP opening. In human PASMC, M and Nsp9 proteins inhibited HPV. In MHV-1 pneumonia, infected AEC displayed apoptosis and HPV was suppressed. BAY K8644, a calcium channel agonist, increased HPV and improved SpO2. CONCLUSIONS: Coronaviruses, including SARS-CoV-2, cause AEC apoptosis, mitochondrial fission, and bioenergetic impairment. SARS-CoV-2 also suppresses HPV by targeting mitochondria. This mitochondriopathy is replicated by transduction with SARS-CoV-2 proteins, indicating a mechanistic role for viral-host mitochondrial protein interactions. Mitochondriopathy is a conserved feature of coronaviral pneumonia that may exacerbate hypoxemia and constitutes a therapeutic target.

Hepatoprotective Effects of Aureobasidium pullulans Derived ß 1,3-1,6 Glucans in a Murine Model of Non-alcoholic Steatohepatitis.

Background: Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are highly prevalent conditions characterized by inflammation and fibrosis of the liver, which can progress to cirrhosis and hepatocellular carcinoma if left untreated. Conventional modalities are mainly symptomatic, with no definite solution. Beta-glucan-based biological response modifiers are a potential strategy in lieu of their beneficial metabolic effects. Aureobasidium pullulans strains AFO-202 and N-163 beta-glucans were evaluated for anti-fibrotic and anti-inflammatory hepatoprotective potentials in a NASH animal model in this study. Methods: In the STAM™ murine model of NASH, five groups were studied for 8 weeks: (1) vehicle (RO water), (2) AFO-202 beta-glucan; (3) N-163 beta-glucan, (4) AFO-202+N-163 beta-glucan, and (5) telmisartan (standard pharmacological intervention). Evaluation of biochemical parameters in plasma and hepatic histology including Sirius red staining and F4/80 immunostaining were performed. Results: AFO-202 beta-glucan significantly decreased inflammation-associated hepatic cell ballooning and steatosis. N-163 beta-glucan decreased fibrosis and inflammation significantly (P value < 0.05). The combination of AFO-202 with N-163 significantly decreased the NAFLD Activity Score (NAS) compared with other groups. Conclusion: This preclinical study supports the potential of N-163 and AFO-202 beta-glucans alone or in combination as potential preventive and therapeutic agent(s), for NASH.

Analyzing trends in obstetrics and gynecology fellowship training over the last decade using the normalized competitive index.

BACKGROUND: The objective and relative competitiveness of obstetrical and gynecologic subspecialty training programs remain understudied. Traditional metrics, such as match rate or program fill rate, fail to standardize the application environment. This limits their applicability when examining demographic trends or when comparing data between different fellowship matches. The normalized competitive index was introduced to serve as a comprehensive metric of competitiveness by incorporating disparate indicators and normalizing to enable more detailed analyses. OBJECTIVE: This study aimed to analyze trends in the competitiveness across obstetrical and gynecologic subspecialty fellowship matches during the last decade. STUDY DESIGN: The results and data reports from the National Resident Match Program fellowship for 2010 to 2019 were used to collect data on multiple metrics of competitiveness for 6 obstetrical and gynecologic subspecialties. These data were used to determine the normalized competitive index. Subanalyses were conducted to identify trends over the last decade. RESULTS: Among fellowship programs in obstetrics and gynecology, the overall specialty match rate was 67.6%. The overall specialty program fill rate was 95.7%. According to the normalized competitive index metric, minimally invasive gynecologic surgery was the most competitive fellowship match (normalized competitive index=1.31; P=.002). Maternal-fetal medicine was the least competitive (normalized competitive index=0.94; P≤.005). When comparing the first and second half of the decade, no specialty experienced a significant decrease in match rate. The only significant increase in match rates occurred for female pelvic medicine and reconstructive surgery (P=.035). Subanalyses of the normalized competitive index metric and other indicators of competitiveness demonstrated a strong negative correlation between the normalized competitive index and the subspecialty match rate (r=-0.9444) and a moderately positive correlation between the normalized competitive index and the program fill rate (r=0.4047). CONCLUSION: The normalized competitive index offers trainees a more quantitative understanding of the fellowship application environment. By incorporating multiple metrics and normalizing the result, it uniquely enables comparison between the subspecialty matches and the match process over time. The same standardization offers the potential for future comparisons of competitiveness within a single subspecialty match based on geographic region, applicant demographics, and other important determinants of a diverse and vibrant training environment.

Two unique biological response-modifier glucans beneficially regulating gut microbiota and faecal metabolome in a non-alcoholic steatohepatitis animal model, with potential applications in human health and disease.

OBJECTIVE: The gut microbiome and its metabolites are influenced by age and stress and reflect the metabolism and health of the immune system. We assessed the gut microbiota and faecal metabolome in a static animal model of non-alcoholic steatohepatitis (NASH). DESIGN: This model was subjected to the following treatments: reverse osmosis water, AFO-202, N-163, AFO-202+N-163 and telmisartan treatment. Faecal samples were collected at 6 and 9 weeks of age. The gut microbiome was analysed using 16S ribosomal RNA sequences acquired by next-generation sequencing, and the faecal metabolome was analysed using gas chromatography-mass spectrometry. RESULTS: Gut microbial diversity increased greatly in the AFO-202+N-163 group. Postintervention, the abundance of Firmicutes decreased, whereas that of Bacteroides increased and was the highest in the AFO-202+N-163 group. The decrease in the abundance of Enterobacteriaceae and other Firmicutes and the abundance of Turicibacter and Bilophila were the highest in the AFO-202 and N-163 groups, respectively. Lactobacillus abundance was highest in the AFO-202+N-163 group. The faecal metabolite spermidine, which is beneficial against inflammation and NASH, was significantly decreased (p=0.012) in the N-163 group. Succinic acid, which is beneficial in neurodevelopmental and neurodegenerative diseases, was increased in the AFO-202 group (p=0.06). The decrease in fructose was the highest in the N-163 group (p=0.0007). Isoleucine and Leucine decreased with statistical significance (p=0.004 and 0.012, respectively), and tryptophan also decreased (p=0.99), whereas ornithine, which is beneficial against chronic immune-metabolic-inflammatory pathologies, increased in the AFO-202+N-163 group. CONCLUSION: AFO-202 treatment in mice is beneficial against neurodevelopmental and neurodegenerative diseases, and has prophylactic potential against metabolic conditions. N-163 treatment exerts anti-inflammatory effects against organ fibrosis and neuroinflammation. In combination, these compounds exhibit anticancer activity.

Evaluation of a gene expression biomarker to identify operationally tolerant liver transplant recipients: the LITMUS trial.

LITMUS was a single-centre, Phase 2a study designed to investigate whether the gene biomarker FGL2/IFNG previously reported for the identification of tolerance in murine models could identify operationally tolerant liver transplant recipients. Multiplex RT-PCR was used to amplify eight immunoregulatory genes in peripheral blood mononuclear cells (PBMC) from 69 adult liver transplant recipients. Patients with PBMC FGL2/IFNG ≥ 1 and a normal liver biopsy underwent immunosuppression (IS) withdrawal. The primary end point was the development of operational tolerance. Secondary end points included correlation of tolerance with allograft gene expression and immune cell markers. Twenty-eight of 69 patients (38%) were positive for the PBMC tolerance biomarker and 23 proceeded to IS withdrawal. Nine of the 23 patients had abnormal baseline liver biopsies and were excluded. Of the 14 patients with normal biopsies, eight (57%) have achieved operational tolerance and are off IS (range 12-57 months). Additional studies revealed that all of the tolerant patients and only one non-tolerant patient had a liver gene ratio of FOXP3/IFNG ≥ 1 prior to IS withdrawal. Increased CD4+ T regulatory T cells were detected both in PBMC and livers of tolerant patients following IS withdrawal. Higher expression of SELE (gene for E-selectin) and lower expression of genes associated with inflammatory responses (GZMB, CIITA, UBD, LSP1, and CXCL9) were observed in the pre-withdrawal liver biopsies of tolerant patients by RNA sequencing. These results suggest that measurement of PBMC FGL2/IFNG may enrich for the identification of operationally tolerant liver transplant patients, especially when combined with intragraft measurement of FOXP3/IFNG. Clinical Trial Registration: ClinicalTrials.gov (LITMUS: NCT02541916).

Impact of Question Bank Use for In-Training Examination Preparation by OBGYN Residents - A Multicenter Study.

OBJECTIVE: To examine the impact of access to and utilization of a commercially available question bank (TrueLearn) for in-training examination (ITE) preparation in Obstetrics and Gynecology (OBGYN). DESIGN: This was a retrospective cohort study examining the impact of TrueLearn usage on ITE examination performance outcomes. Produced by the educational arm of the American College of Obstetricians and Gynecologists, the Council on Resident Education in Obstetrics and Gynecology (CREOG) exam is a multiple-choice test given to all residents annually. Residency programs participating in this study provided residency program mean CREOG scores from the year prior (2015), and the first (2016) and second (2017) years of TrueLearn usage. Programs also contributed resident-specific CREOG scores for each resident for 2016 and 2017. This data was combined with each resident's TrueLearn usage data that was provided by TrueLearn with residency program consent. The CREOG scores consisted of the CREOG score standardized to all program years, the CREOG score standardized to the same program year (PGY) and the total percent (%) correct. TrueLearn usage data included number of practice questions completed, number of practice tests taken, average number of days between successive tests, and percent correct of answered practice questions. SETTING: OBGYN Residency Training Programs. PARTICIPANTS: OBGYN residency programs that purchased and utilized TrueLearn for the 2016 CREOG examination were eligible for participation (n = 14). Ten residency programs participated, which consisted of 212 residents in 2016 and 218 residents in 2017. RESULTS: TrueLearn was used by 78.8% (167/212) of the residents in 2016 and 84.9% (185/218) of the residents in 2017. No significant difference was seen in the average CREOG scores available on a per- program level before versus after the first year of implementation either using the CREOG score standardized to all PGYs (mean difference 1.0; p = 0.58) or standardized to the same PGY (mean difference 3.1; p = 0.25). Using resident-level data, there was no significant difference in mean CREOG score standardized to all PGYs between users and non-users of TrueLearn in 2016 (mean, 199.4 vs 196.7; p = 0.41) or 2017 (mean, 198.2 vs 203.4; p = 0.19). The percent of practice questions answered correctly on TrueLearn was positively correlated with the CREOG score standardized to all PGYs (r = 0.47 for 2016 and r = 0.60 for 2017), as well as with the CREOG total percent correct (r = 0.47 for 2016 and r = 0.61 for 2017). Based on a simple linear regression, for every 500 practice questions completed, the CREOG score significantly increased for PGY-2 residents by an average (±SE) of 7.3 ± 2.8 points (p = 0.013); the average increase was 0.7 ± 2.5 (p = 0.79) for PGY-3 residents and 5.8 ± 3.3 points (p = 0.09) for PGY-4 residents. CONCLUSIONS: Adoption of an online question bank did not result in higher mean CREOG scores at participating institutions. However, performance on the TrueLearn questions correlated with ITE performance, supporting predictive validity and the use of this question bank as a formative assessment for resident education and exam preparation.

Autologous Hematopoietic Stem Cell Transplantation for Liver Transplant Recipients With Recurrent Primary Sclerosing Cholangitis: A Pilot Study.

BACKGROUND: Primary sclerosing cholangitis (PSC) is an indication for liver transplantation, but recurrence after liver transplantation is associated with poor outcomes often requiring repeat transplantation. We investigated whether autologous hematopoietic stem cell transplantation (aHSCT) could be used to stop progression of recurrent PSC and promote operational tolerance. METHODS: Twelve patients with recurrent PSC were fully evaluated and 5 were selected for aHSCT. Autologous hematopoietic stem cells were collected, purified by CD34 immunomagnetic selection, and cryopreserved. Immunoablation using busulfan, cyclophosphamide, and rabbit antithymocyte globulin was followed by aHSCT. The primary endpoint of the study was the establishment of operational tolerance defined as lack of biochemical, histologic, and clinical evidence of rejection while off immunosuppression at 2 y post-aHSCT. RESULTS: Two of the 5 patients achieved operational tolerance with no clinical or histologic evidence of PSC progression or allorejection. A third patient developed sinusoidal obstruction syndrome following aHSCT requiring repeat liver transplantation but has no evidence of PSC recurrence while on sirolimus monotherapy now >3 y after aHSCT. A fourth patient was weaned off immunosuppression but died 212 d after aHSCT from pericardial constriction. A fifth patient died from multiorgan failure. Immunosuppression-free allograft acceptance was associated with deletion of T-cell clones, loss of autoantibodies, and increases in regulatory T cells, transitional B cells, and programmed cell death protein-1 expressing CD8+ T cells in the 2 long-term survivors. CONCLUSIONS: Although operational tolerance occurred following aHSCT, the high morbidity and mortality observed render this specific protocol unsuitable for clinical adoption.

Beneficial effects of novel aureobasidium pullulans strains produced beta-1,3-1,6 glucans on interleukin-6 and D-dimer levels in COVID-19 patients; results of a randomized multiple-arm pilot clinical study.

OBJECTIVE: In this pilot clinical study, we report the beneficial effects of beta glucans derived from two strains AFO-202 and N-163 of a black yeast Aureobasidium pullulans on the biomarkers for cytokine storm and coagulopathy in COVID-19 patients. METHODS: A total of 24 RT-PCR positive COVID-19 patients were recruited and randomly divided into three groups (Gr): Gr. 1 control (n = 8) - Standard treatment; Gr. 2: Standard treatment + AFO-202 beta glucan (n = 8); and Gr. 3, Standard treatment + combination of AFO-202 and N-163 beta glucans (n = 8) for 30 days. RESULTS: There was no mortality or requirement of ventilation of the subjects in any of the groups. There was a decrease in D-Dimer values (751 ng/ml to 143.89 ng/ml) and IL-6 values (7.395-3.16 pg/ml) in Gr. 1 in 15 days but the levels increased to abnormal levels on day 30 (D-Dimer: 202.5 ng/ml; IL-6 55.37 pg/ml); which steadily decreased up to day 30 in groups 2 (D-dimer: 560.99 ng/dl to 79.615; IL-6: 26.18-3.41 pg/ml) and 3 (D-dimer: 1614 ng/dl to 164.25 ng/dl; IL-6: 6.25-0.5 pg/ml). The same trend was observed with ESR. LCR and LeCR increased while NLR decreased significantly in Gr. 3. CD4 + and CD8 + T cell count showed relatively higher increase in Gr.3. There was no difference in CRP within the groups. CONCLUSION: As these beta glucans are well known food supplements with a track record for safety, larger multi-centric clinical studies are recommended to validate their use as an adjunct in the management of COVID-19 and the ensuing long COVID-19 syndrome.

Effects of different frozen embryo transfer regimens on abnormalities of fetal weight: a systematic review and meta-analysis.

BACKGROUND: Reported increases in maternal and perinatal morbidity (including macrosomia, large for gestational age (LGA), cesarean section, hemorrhage and hypertensive disorders of pregnancy) following frozen embryo transfer (FET) cycles may be associated with the lack of a corpus luteum seen in programmed FET. Given the growing number of studies comparing outcomes between natural FET and programmed FET cycles, a meta-analysis would prove useful to detect the presence of abnormalities in fetal birth weight in patients undergoing natural and programmed FET cycles. OBJECTIVE AND RATIONALE: The aim of this study was to provide a systematic review and meta-analysis of the effects of natural versus programmed methods of endometrial preparation for FET cycles on fetal weight and the risks of LGA and macrosomia. SEARCH METHODS: A literature search using MEDLINE, SCOPUS, EMBASE and clinicaltrials.gov was conducted for published research comparing neonatal outcomes in natural FET and programmed FET cycles. Primary outcomes of interest were fetal weight, macrosomia and LGA. Studies were included if the following criteria were met: study contained cohorts of NFET and programmed FET with outcome data of birth weight, large for gestational data and/or macrosomia. The data are presented as average weight and odds ratio (OR) with 95% confidence interval (CI) with fixed- or random-effects meta-analysis between cohorts of NFET and programmed FET cycles. Bias was assessed using Newcastle-Ottawa quality assessment scale for the 14 included studies. Multiple subgroup analyses were performed to assess for effect of the true natural cycle (defined as no ovulation trigger medication use) and the day of embryo transfer on fetal weight parameters compared with programmed cycle FET. OUTCOMES: A total of 879 studies were identified, with 15 meeting inclusion the criteria. The studies varied with respect to country of origin, definition of natural cycle FET and type of progesterone supplementation used. The included studies had similar gestational ages at the time of birth. Programmed FET cycles resulted in a higher fetal weight compared with natural FET cycles (mean difference 47.38 gp = 0.04). Programmed FET cycles were also at higher risk for macrosomia (OR 1.15, 95% CI 1.06-1.26) and LGA (OR 1.10, 95% CI 1.02-1.19) compared with natural FET cycles. Subgroup analyses demonstrated that programmed FET cycles resulted in a higher fetal weight compared with true natural FET (mean difference 62.18 gp = 0.0001) cycles. Cleavage stage embryo transfers had an increased risk of LGA (OR 1.27, 95% CI 1.00-1.62) and an increased risk of macrosomia (OR 1.25, 95% CI 1.08-1.44) in programmed FET cycles compared with natural FET cycles. Blastocyst transfer in programmed FET cycles resulted in no difference in risk of macrosomia but an increased risk of LGA (OR 1.13, 95% CI 1.06-1.21) compared with natural FET cycles. WIDER IMPLICATIONS: Programmed endometrial preparation for FET cycles had a significant effect, causing increased fetal birth weight and increased risks of LGA and macrosomia. The numbers of studies in the subgroup analyses were too low to determine reliable results. Further prospective randomized trials are needed to determine whether the changes seen in the observational trials are indeed accurate.

Elevated Serum Estradiol Levels Do Not Inhibit Implantation During Frozen Embryo Transfer Cycles.

The aim of the study is to determine if the magnitude of serum estradiol levels in blastocyst frozen embryo transfer cycles are associated with clinical pregnancy. A retrospective cohort study of female patients 18-43 years old, who underwent vitrified blastocyst embryo transfers at Tripler Army Medical Center from October 1, 2006, to October 1, 2016, was evaluated to determine the impact of estradiol levels on ongoing pregnancy rates in frozen embryo transfer cycles. The study included 173 total frozen embryo transfer cycles during the 10-year study period. The mean age at time of transfer was 34.5 years old (±4.4) with a majority of women undergoing double embryo transfer (70%). There was no statistical difference in ongoing pregnancy rates across estradiol levels (p = 0.80). However, at estradiol levels >3000 pg/mL, a statistically significant ongoing pregnancy rate was observed (p = 0.009). Ongoing pregnancy rate in frozen embryo transfer cycles is not negatively impacted by elevated estradiol levels.

Efficacy and Safety of Everolimus With Reduced Tacrolimus in Liver Transplant Recipients: 24-month Results From the Pooled Analysis of 2 Randomized Controlled Trials.

BACKGROUND AND METHODS: Data from 2 randomized liver transplant trials (N = 772; H2304 [deceased donor, n = 488], H2307 [living donor, n = 284]) were pooled to further evaluate the efficacy and safety of everolimus with reduced tacrolimus (EVR + rTAC) versus standard tacrolimus (sTAC) regimen at month 24. RESULTS: EVR + rTAC was comparable to sTAC for composite efficacy failure of treated biopsy-proven acute rejection, graft loss, or death (9.8% versus 10.8%; difference, -1.0%; 95% confidence interval, -5.4 to 3.4; P = 0.641) at month 24. EVR + rTAC was superior to sTAC for the mean change in estimated glomerular filtration rate (eGFR) from randomization to month 24 (-8.37 versus -13.40 mL/min/1.73 m2; P = 0.001). A subanalysis of renal function by chronic kidney disease (CKD) stage at randomization showed significantly lower decline in eGFR from randomization to month 24 for patients with CKD stage 1/2 (eGFR ≥ 60 mL/min/1.73 m2) in EVR + rTAC group versus sTAC (-12.82 versus -17.67 mL/min/1.73 m2, P = 0.009). In patients transplanted for hepatocellular carcinoma (HCC) beyond Milan criteria, HCC recurrence was numerically lower although not statistically significant with EVR + rTAC versus sTAC group (5.9% [1 of 17] versus 23.1% [6 of 26], P = 0.215), while comparable in patients within Milan criteria (2.9% [3 of 102] versus 2.1% [2 of 96], P = 1.000), irrespective of pretransplant alpha-fetoprotein levels. CONCLUSIONS: EVR + rTAC versus sTAC showed comparable efficacy and safety with significantly better renal function, particularly in patients with normal/mildly decreased renal function (CKD stage 1/2) at randomization and a trend toward lower HCC recurrence in patients transplanted with HCC beyond Milan at month 24. Further long-term data would be required to confirm these results.

Single Embryo Transfer Versus Double Embryo Transfer: A Cost-Effectiveness Analysis in a Non-IVF Insurance Mandated System.

INTRODUCTION: Because of increased morbidity seen in multiple gestations, the American Society of Reproductive Medicine recommends transfer of blastocysts one at a time for most patients. While cost-effectiveness models have compared single embryo transfer (SET) versus double embryo transfer (DET), few incorporate maternal and neonatal morbidity, and none have been performed in U.S. Military facilities. The purpose of this study was to determine the cost effectiveness of sequential SET versus DET in a U.S. Military treatment facility. MATERIALS AND METHODS: A cost-effectiveness model was created based on 250 patients between the ages of 20-44 who previously underwent in vitro fertilization (IVF) at our facility. The model consisted of patients pursuing either SET or DET with two total embryos. Cycle outcomes were determined using the published SARTCORS success calculator. Neonatal and obstetrical outcomes were simulated based on singleton and twin IVF pregnancies. Neonatal and obstetrical cost estimates were based on internal data as well. RESULTS: If 250 model patients pursue SET, 140 live births would occur, with total cost of $5.7 million, and cost per delivery of $40,500. If the model patients pursued DET, 117 live births would occur, with total cost of $9.2 million and a cost per delivery of $77.700. DET would lead to more total infants (207 vs. 143 in SET cohort). Personal costs are higher in SET versus DET cohorts ($23,036 vs. $20,535). CONCLUSIONS: SET in a system with no infertility coverage saves approximately $3.5 million per 250 patients. Higher personal costs as seen with SET may incentivize patients to seek DET. The total savings should encourage alteration to practice patterns with the U.S Military Healthcare System.

Azoospermia Secondary to a Novel X-Autosomal Reciprocal Translocation: 46,Y, t(X:16)(p22.1:p11.2).

Chromosomal translocations occur in 10 to 15% of men with azoospermia. Thirty distinct X-autosomal balanced reciprocal translocations have been reported in the literature thus far. We present a novel case of azoospermia with a karyotype of 46,Y,t(X:16)(p22.1:p11.2). A 26-year-old, healthy, active duty male Solider presented with his dependent female partner for primary infertility. Female anatomical and endocrine evaluations were normal. Initial male evaluation revealed azoospermia on multiple semen analyses. Further evaluation with a detailed physical exam and laboratory tests were normal except for an abnormal karyotype with a reciprocal translocation at chromosomes X and 16. An open testicular biopsy demonstrated 75% late spermatid maturation arrest confirming reproductive potential although significantly reduced. Men who present with azoospermia should undergo a full endocrine and genetic evaluation with a thorough physical evaluation by an urologist. They can have limited but successful reproductive outcomes if spermatozoa can be isolated during testicular biopsy. Given the high risk of producing genetically unbalanced embryos, genetic counseling and preimplantation genetic testing is essential before pursuing assisted reproductive technology. This case is the first X-autosomal balanced reciprocal translocations involving chromosome 16 and highlights the importance of the X chromosome during spermatogenesis.