Human factor engineering of point-of-care near infrared spectroscopy device for intracranial hemorrhage detection in Traumatic Brain Injury: A multi-center comparative study using a hybrid methodology.

OBJECTIVE: This study assessed machine learning powered Near-infrared spectroscopy based (mNIRS) device's usability and human factor ergonomics in four distinct healthcare provider groups. BACKGROUND: Traumatic Brain Injury (TBI) is a global concern with significant well-being implications. Timely intracranial hemorrhage (ICH) detection is crucial. mNIRS offers efficient non-invasive TBI screening. METHODS: Two device utilization stages involved operators (N = 21) and TBI-suspected subjects (n = 120). A hybrid approach used qualitative and quantitative methods, utilizing a 57-item survey and task completion time. RESULTS: All groups positively perceived user-interface, physical, cognitive, and organizational ergonomics. The device's ease of use, calibration, size, cognitive support, and integration gained appreciation. Training reduced task completion time from 16.5 to 13.2 s. CONCLUSION: mNIRS-based CEREBO® proves usable for TBI point-of-care assessment. Positive feedback from diverse healthcare groups validates design and cost-effectiveness alignment. A hybrid approach, training, and practice scans enhance usage and experience.

Evaluating CAPO®: A biocompatibility, transparency, and fitment assessment for use with CEREBO® in traumatic intracranial injury detection.

Healthcare-associated infections (HAIs) are a global concern affecting millions of patients, requiring robust infection prevention and control measures. In particular, patients with traumatic brain injury (TBI) are highly susceptible to nosocomial infections, emphasizing the importance of infection control. Non-invasive near infrared spectroscopy (NIRS) device, CEREBO® integrated with a disposable component CAPO® has emerged as a valuable tool for TBI patient triage and this study evaluated the safety and efficacy of this combination. Biocompatibility tests confirmed safety and transparency assessments demonstrated excellent light transmission. Clinical evaluation with 598 enrollments demonstrated high accuracy of CEREBO® in detecting traumatic intracranial hemorrhage. During these evaluations, the cap fitted well and moved smoothly with the probes demonstrating appropriate flexibility. These findings support the efficacy of the CAPO® and CEREBO® combination, potentially improving infection control and enhancing intracranial hemorrhage detection for TBI patient triage. Ultimately, this can lead to better healthcare outcomes and reduced global HAIs.

Metabolic imaging of human embryos is predictive of ploidy status but is not associated with clinical pregnancy outcomes: a pilot trial.

STUDY QUESTION: Does fluorescence lifetime imaging microscopy (FLIM)-based metabolic imaging assessment of human blastocysts prior to frozen transfer correlate with pregnancy outcomes? SUMMARY ANSWER: FLIM failed to distinguish consistent patterns in mitochondrial metabolism between blastocysts leading to pregnancy compared to those that did not. WHAT IS KNOWN ALREADY: FLIM measurements provide quantitative information on NAD(P)H and flavin adenine dinucleotide (FAD+) concentrations. The metabolism of embryos has long been linked to their viability, suggesting the potential utility of metabolic measurements to aid in selection. STUDY DESIGN, SIZE, DURATION: This was a pilot trial enrolling 121 IVF couples who consented to have their frozen blastocyst measured using non-invasive metabolic imaging. After being warmed, 105 couples' good-quality blastocysts underwent a 6-min scan in a controlled temperature and gas environment. FLIM-assessed blastocysts were then transferred without any intervention in management. PARTICIPANTS/MATERIALS, SETTING, METHODS: Eight metabolic parameters were obtained from each blastocyst (4 for NAD(P)H and 4 for FAD): short and long fluorescence lifetime, fluorescence intensity, and fraction of the molecule engaged with enzyme. The redox ratio (intensity of NAD(P)H)/(intensity of FAD) was also calculated. FLIM data were combined with known metadata and analyzed to quantify the ability of metabolic imaging to differentiate embryos that resulted in pregnancy from embryos that did not. De-identified discarded aneuploid human embryos (n = 158) were also measured to quantify correlations with ploidy status and other factors. Statistical comparisons were performed using logistic regression and receiver operating characteristic (ROC) curves with 5-fold cross-validation averaged over 100 repeats with random sampling. AUC values were used to quantify the ability to distinguish between classes. MAIN RESULTS AND THE ROLE OF CHANCE: No metabolic imaging parameters showed significant differences between good-quality blastocysts resulting in pregnancy versus those that did not. A logistic regression using metabolic data and metadata produced an ROC AUC of 0.58. In contrast, robust AUCs were obtained when classifying other factors such as comparison of Day 5 (n = 64) versus Day 6 (n = 41) blastocysts (AUC = 0.78), inner cell mass versus trophectoderm (n = 105: AUC = 0.88) and aneuploid (n = 158) versus euploid and positive pregnancy embryos (n = 108) (AUC = 0.82). LIMITATIONS, REASONS FOR CAUTION: The study protocol did not select which embryo to transfer and the cohort of 105 included blastocysts were all high quality. The study was also limited in number of participants and study sites. Increased power and performing the trial in more sites may have provided a stronger conclusion regarding the merits of the use of FLIM clinically. WIDER IMPLICATIONS OF THE FINDINGS: FLIM failed to distinguish consistent patterns in mitochondrial metabolism between good-quality blastocysts leading to pregnancy compared to those that did not. Blastocyst ploidy status was, however, highly distinguishable. In addition, embryo regions and embryo day were consistently revealed by FLIM. While metabolic imaging detects mitochondrial metabolic features in human blastocysts, this pilot trial indicates it does not have the potential to serve as an effective embryo viability detection tool. This may be because mitochondrial metabolism plays an alternative role post-implantation. STUDY FUNDING/COMPETING INTEREST(S): This study was sponsored by Optiva Fertility, Inc. Boston IVF contributed to the clinical site and services. Becker Hickl, GmbH, provided the FLIM system on loan. T.S. was the founder and held stock in Optiva Fertility, Inc., and D.S. and E.S. had options with Optiva Fertility, Inc., during this study. TRIAL REGISTRATION NUMBER: The study was approved by WCG Connexus IRB (Study Number 1298156).

Perinatal outcomes in 6640 singleton pregnancies after donor oocyte IVF across three continents over 7 years.

PURPOSE: Are trends in singleton donor oocyte IVF perinatal outcomes consistent over time among four international ethnically diverse infertility centers? METHODS: This retrospective cohort consisted of an infertility network of four international IVF centers across three continents. Singleton live births resulting from fresh and frozen donor oocyte embryo transfers from January 1, 2012 to December 31, 2018 were included. The main outcome measures were birth weight (BW), preterm birth (PTB), large for gestational age (LGA), small for gestational age (SGA) and gestational age (GA) at delivery. RESULTS: The entire cohort (n = 6640) consisted of 4753 fresh and 1887 frozen donor oocyte embryo transfers. Maternal age, parity, body mass index, neonatal sex and GA at delivery were similar for fresh and frozen donor oocyte embryo transfers in the entire cohort and within each infertility center. All four centers had a trend of decreased BW and rates of PTB before 32 weeks annually, although significance was not reached. Three of the four centers had annual increased trends of PTB before 37 weeks and LGA newborns, although significance was not reached. BWs for the entire cohort for fresh and frozen donor embryo transfers were 3166 g ± 601 g and 3137 g ± 626 g, respectively. CONCLUSION: Similar trends in perinatal outcomes were present across four international infertility centers over 7 years. The overall perinatal trends in donor oocyte IVF may be applicable to centers worldwide, but further studies in more geographic regions are needed.

Perinatal outcomes in 13,626 singleton pregnancies after autologous IVF across three continents over 7 years.

PURPOSE: Are trends in singleton autologous IVF perinatal outcomes consistent over time among five international infertility centers? METHODS: This was a retrospective cohort study from January 1, 2012, to December 31, 2018. This study was performed through a large infertility network at five international infertility centers in which patients who had a singleton live birth resulting from fresh and frozen autologous IVF cycles were included. The primary outcome was live birth weight (BW) with secondary outcomes of preterm birth (PTB), large for gestational age (LGA), small for gestational age (SGA), and gestational age at delivery. RESULTS: The entire cohort (n = 13,626) consisted of 6941 fresh and 6685 frozen autologous IVF cycles leading to singleton deliveries. Maternal age, parity, body mass index, neonatal sex, and GA at delivery were similar for fresh and frozen IVF cycles in the entire cohort and within each infertility center. Four centers had a trend of decreased BW and three centers had decreased rates of PTB before 32 and 28 weeks and LGA newborns annually, although significance was not reached. Three IVF centers had annual increased trends of PTB before 37 weeks and four centers had increased rates of SGA newborns, although significance was not reached. CONCLUSION: Similar trends in perinatal outcomes were present across five international infertility centers over 7 years. Additional studies are crucial to further assess and optimize perinatal outcomes at an international level.

From oocytes to a live birth: Are we improving the biological efficiency?

OBJECTIVE(S): The objectives of our study were to investigate the live birth rate (LBR) per oocyte retrieved during in vitro fertilization, in patients who had used all their embryos and to extrapolate the LBR in patients with remaining frozen embryos by calculating the expected LBR from these embryos. DESIGN: A retrospective cohort study. SETTING: A single academically affiliated fertility clinic. PATIENT(S): Autologous in vitro fertilization cycles from January 2014 to December 2020. Data on the number of oocytes retrieved, number of embryos obtained and transferred (at cleavage or blastocyst-stage), use of preimplantation genetic testing for aneuploidy (PGT-A), and number of live births were obtained. The expected LBR was estimated in patients with remaining frozen embryos according to nationally reported Society for Assisted Reproductive Technology LBR data. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Live birth rate per oocyte retrieved. RESULT(S): A total of 12,717 patients met the inclusion criteria and underwent a total of 20,677 oocyte retrievals which yielded a total of 248,004 oocytes and 57,268 embryos (fresh and frozen). In patients who had fully utilized all their embryos the LBR per oocyte was 2.82% (ranging from 11.3% aged <35 years to 1.2% aged >42 years). Stratification of the population based on PGT-A utilization yielded similar results (with PGT-A: 2.88% and without PGT-A: 2.79%). When stratified by the Society for Assisted Reproductive Technology age groups, the addition of PGT-A in patients aged 35-37 and 38-40 years yielded higher LBR per oocyte compared with patients who did not add PGT-A (P<.05). In patients with remaining frozen embryos who had added PGT-A, the projected LBR per oocyte was 8.34%. Use of PGT-A in patients aged <35 and 35-37 years decreased LBR per oocyte (P<.001 and P=.03, respectively) but improved LBR per oocyte in patients aged 38-40 and 41-42 years (P=.006 and P=.005, respectively). Poisson regression analysis demonstrated an age threshold of 38.5, below which PGT-A lowers LBR per oocyte compared with no PGT-A. CONCLUSION(S): Despite clinical and scientific advances in Assisted Reproductive Technology, with the current protocols of ovarian stimulation, the LBR per oocyte remains low reflecting a biological barrier that has yet to be overcome. Overall, the addition of PGT-A did not demonstrate improved outcomes.

Advancing edema detection: Harnessing the power of machine learning and near infrared spectroscopy for cerebral and cerebellar edema assessment.

Edema, characterized by brain swelling, is a common response observed in various brain injuries. Timely detection of edema is crucial to mitigate the associated risks and improve patient care. This study evaluates the efficacy of CEREBO®, a non-invasive machine learning-powered near-infrared spectroscopy (mNIRS) based device, in detecting edema. The study was conducted on 234 participants with suspected head injuries who underwent simultaneous CEREBO® scans and CT head scans. The results of the study showed that CEREBO® effectively identified edematous lobes, achieving a sensitivity of 95.7%, specificity of 97%, and accuracy of 96.9% for cases with intracranial hemorrhage (ICH). Additionally, for cases without ICH, the device exhibited a sensitivity of 100%, specificity of 97.2%, and accuracy of 97.2%. Two cases were reported where CEREBO® failed to detect edematous ICH. The study highlights the potential of CEREBO® as a valuable tool for early detection of pre-symptomatic edema and ICH, enabling timely interventions and improved patient care. The findings support the reliability of near-infrared spectroscopy as a diagnostic modality for edema.

Randomized double-blind personalized N-of-1 clinical trial to test the safety and potential efficacy of TJ-68 for treating muscle cramps in amyotrophic lateral sclerosis (ALS): study protocol for a TJ-68 trial.

INTRODUCTION/AIMS: Muscle cramps are a common and often disabling symptom in amyotrophic lateral sclerosis (ALS), a devastating and incurable neurodegenerative disorder. To date, there are no medications specifically approved for the treatment of muscle cramps. Ameliorating muscle cramps in ALS may improve and sustain quality of life. A widely prescribed traditional Japanese (Kampo) medicine against muscle cramps, shakuyakukanzoto (TJ-68), has been studied in advanced liver disease, spinal stenosis, kidney failure, and diabetic neuropathy. The Japanese ALS Management Guideline mentions TJ-68 for difficult muscle cramps in ALS. Therefore, the rationale of our trial is to investigate the safety and effectiveness of TJ-68 in treating painful and disabling muscle cramps in people with ALS outside of Japan. Accordingly, we are conducting a randomized clinical trial to test the safety and efficacy of TJ-68 in participants with ALS reporting frequent muscle cramps using an innovative, personalized N-of-1 design. If successful, TJ-68 may be used for muscle cramps in a broader population of people with ALS. METHODS: This is a two-site, double-blind, randomized personalized N-of-1 early clinical trial with TJ-68. At least 22 participants with ALS and daily muscle cramps will receive drug or placebo for 2 weeks (one treatment period) followed by a 1-week washout in a four-period cross-over design. While the primary objective is to evaluate the safety of TJ-68, the study has 85% power to detect a one-point shift on the Visual Analog Scale for Muscle Cramps Affecting Overall Daily Activity of the Columbia Muscle Cramp Scale (MCS). Secondary outcomes include the full MCS score, a Cramp Diary, Clinical Global Impression of Changes, Goal Attainment Scale, quality of life scale and ALS functional rating scale-revised (ALSFRS-R). DISCUSSION: The study is underway. A personalized N-of-1 trial design is an efficient approach to testing medications that alleviate muscle cramps in rare disorders. If TJ-68 proves safe and efficacious then it may be used to treat cramps in ALS, and help to improve and sustain quality of life. TRIAL REGISTRATION: This clinical trial has been registered with ClinicalTrials.gov (NCT04998305), 8/9/2021.

A Local and Abscopal Effect Observed with Liposomal Encapsulation of Intratumorally Injected Oncolytic Adenoviral Therapy.

This study evaluated the in vivo therapeutic efficacy of oncolytic serotype 5 adenovirus TAV255 in CAR-deficient tumors. In vitro experiments were performed with cell lines that expressed different levels of CAR (HEK293, A549, CT26, 4T1, and MCF-7). Low CAR cells, such as CT26, were poorly transduced by Ad in vitro unless the adenovirus was encapsulated in liposomes. However, the CT26 tumor in an immune-competent mouse model responded to the unencapsulated TAV255; 33% of the tumors were induced into complete remission, and mice with complete remission rejected the rechallenge with cancer cell injection. Encapsulation of TAV255 improves its therapeutic efficacy by transducing more CT26 cells, as expected from in vitro results. In a bilateral tumor model, nonencapsulated TAV255 reduced the growth rate of the locally treated tumors but had no effect on the growth rate of the distant tumor site. Conversely, encapsulated TAV255-infected CT26 induced a delayed growth rate of both the primary injected tumor and the distant tumor, consistent with a robust immune response. In vivo, intratumorally injected unencapsulated adenoviruses infect CAR-negative cells with only limited efficiency. However, unencapsulated adenoviruses robustly inhibit the growth of CAR-deficient tumors, an effect that constitutes an 'in situ vaccination' by stimulating cytotoxic T cells.

CEREBO®: A Portable Device for Non-invasive Detection of Intracranial Hematomas in Real Time.

Context: Brain injury has become a silent epidemic and has very low survival and recovery rates because of inaccurate triaging, especially in absence of symptoms. Therefore, a clinical assessment tool for quick onsite detection of intracranial hematoma is necessary. Aims: This study aims to assess the efficacy of the near infrared-based device CEREBO® for the non-invasive detection of intracranial hematomas in traumatic head injury patients. Settings and Design: Observational, prospective, cohort, single-center study. Methods and Materials: Forty-four patients recruited from the Department of Neurosurgery of Civil Hospital, Ahmedabad, between 3 and 85 years from June 2018 to March 2020 were examined by CEREBO® and computed tomography (CT) scan within 72 h post-injury or first onset of symptoms to measure the desired parameters. Statistical Analysis Used: SAS 9.4. Results: The device exhibited high sensitivity (94.87%) and specificity (76.19%) for unilateral hematomas with a positive predictive value (PPV) of 93.67% and a negative predictive value (NPV) of 80%. For bilateral hematomas, the device exhibited a sensitivity of 80%, specificity of 77.78%, PPV 83.33%, and NPV 73.68%. Conclusions: This study establishes the efficacy of CEREBO® to be used as a point-of-care medical screening device for detecting brain hematomas in patients who have had a head injury and is therefore recommended as an adjunct to CT scan. In the triaging or diagnosis phase, it allows for early treatment and thus helps to reduce the secondary injury resulting from the existing and delayed hematomas.

Simulation-based training for embryo transfer for clinicians with differing levels of expertise: an application of the American Society for Reproductive Medicine Embryo Transfer Simulator.

Objective: To compare the learning curve of clinicians with different levels of embryo transfer (ET) experience using the American Society for Reproductive Medicine (ASRM) Embryo Transfer Simulator. Design: Prospective cohort study. Setting: Single large university-affiliated in vitro fertilization center. Patients: Participants with 3 levels of expertise with ET were recruited: "group 1" (Reproductive Endocrinology and Infertility attendings), "group 2" (Reproductive Endocrinology and Infertility nurses, advance practice providers, or medical assistants), and "group 3" (Obstetrics and Gynecology resident physicians). Interventions: All participants completed ET simulation training using uterine cases A, B, and C (easiest to most difficult) of the ASRM ET Simulator. Participants completed each case 5 times for a total of 15 repetitions. Main Outcome Measures: The primary outcome was ET simulation scores analyzed at each attempt for each uterine case, with a maximum score of 155. Secondary outcomes included self-assessed comfort levels before and after the completion of the simulation and total duration of ET. Comfort was assessed using a 5-point Likert scale. Results: Twenty-seven participants with 3 different levels of expertise with ET were recruited from December 2020 to February 2021. For cases A and B, median total scores were not significantly different between groups 1 and 3 at first or last attempts. Group 2 did not perform as well as group 3 at the beginning of case A or group 1 at the end of case B. All groups demonstrated a decrease in total time from the first attempt to the last attempt for both cases. For case C, the "difficult" uterus, groups 2 and 3 exhibited the greatest improvement in total median score: from 0 to 75 from the first to last attempt. Group 1 scored equally well from first through last attempts. Although no one from group 2 or 3 achieved a passing score with the first attempt (80% of the max score), approximately 30% had passing scores at the last attempt. Groups 1 and 3 showed a significant decrease in total time across attempts for case C. Following simulation, 100% of groups 2 and 3 reported perceived improvement in their skills. Group 3 showed significant improvement in comfort scores with Likert scores of 1.71 ± 0.76 and 1.0 ± 0.0 for the "Easy" and "Difficult" cases, respectively, before simulation and 4.57 ± 0.53 and 2.4 ± 1.1 after simulation. Conclusions: The ASRM ET Simulator was effective in improving both technical skill and comfort level, particularly for those with little to no ET experience and was most marked when training on a difficult clinical case.

Primary lateral sclerosis natural history study - planning, designing, and early enrollment.

Introduction/Aims. Primary lateral sclerosis (PLS) is exceedingly rare and has been an enigmatic disease. Recent progress has drastically changed this perception, with early biomarkers being investigated and potential medications for PLS emerging at the preclinical stage. The aim of this paper is to describe a study of PLS natural history and discuss the limitations and proposed solutions to the study of a rare and slowly progressive disease. Methods. The PLS Natural History Study is a 30-site, 24-month, prospective study that is supported by multiple funding sources. The study aims to enroll 50 early PLS (disease duration ≤4 years) and 50 definite PLS (disease duration 4 to 15 years) participants using modified PLS Diagnostic Criteria. Smartphone-based assessments including semi-quantitative and quantitative measures and patient-reported outcomes are utilized. In-person quantitative measures are also completed during site visits. The change in the PLS Functional Rating Scale score is the primary outcome. The study utilizes the NeuroBANK® patient-centric data capture and management platform. The biostatistical analysis plan has been developed. Results. In one year, 28 participants have been recruited. Enrollment has been much slower than anticipated due to the COVID-19 pandemic, the rarity of PLS, and potential study competition for internal resources from ALS clinical trials. Discussion. We discuss the need for more innovative methods to enroll and study individuals with such rare diseases and propose a number of mechanisms by which more efficient enrollment could be facilitated.

A unique presentation of Crouzon-like syndrome: Complex craniosynostosis in the absence of genetic mutations or familial predisposition - A case report.

Background: Crouzon syndrome is a rare genetic disorder characterized by premature fusion of skull sutures during skull development, resulting in various craniofacial abnormalities and complex craniosynostosis is a condition in which more than one such sutures of the skull fuse prematurely. Case Description: Herein, we present a case of a 5-year-old male diagnosed with Crouzon-like syndrome and complex craniosynostosis involving multiple cranial sutures, including metopic, sagittal, coronal (right and left), and lambdoid sutures, and without any identifiable mutations on karyotyping. The patient underwent successful surgical intervention with a satisfactory outcome, highlighting the importance of early diagnosis and intervention to prevent or minimize associated neurological manifestations and craniofacial abnormalities. Conclusion: Our case report underscores the involvement of multiple cranial sutures in complex craniosynostosis and the absence of identifiable mutations or family history of similar craniofacial abnormalities, providing important insights into the diagnosis and management of this condition.

Emergence of Cerebral Mucormycosis in the Post-COVID Period: A Detailed Analysis of Risk Factors, Clinical Progression, and Management of This Opportunistic Fungal Infection.

BACKGROUND: An epidemic of Mucorales was reported following the second wave of COVID-19 in India, and intracranial extension of the same was one of the most dreadful complications. METHODS: A total of 62 patients with cerebral mucormycosis were recruited and followed up till 12 weeks to evaluate the risk factors, incidence, clinical manifestations, management, and prognosis of cerebral mucormycosis. FINDINGS: A median age of 51.5 years with male predominance (74%) was noted. The majority of subjects reported a history of COVID infection (93.5%) and diabetes mellitus (83.87%). The first symptom of mucormycosis appeared after a mean period of 17.63 ± 8.9 days following COVID. Facial swelling and ptosis were the most common symptoms. Only 55% of patients had neurological presentations, and hemiparesis was the most common neurological sign (30.6%). Radiologically, the involvement of maxillary sinus (90.32%) and ethmoid sinus (87.10%) was commonly noted. Cerebral findings included temporal lobe (50%) and parietal lobe (30.06%) involvement, cavernous sinus thrombosis (30.06%), and internal carotid artery thrombosis (22.58%). Acute cerebral infarction was notable in 37% of subjects (p-value=0.0015, significant association with the outcome). Conventional and liposomal amphotericin B were used in 91.94% and 53.23% of patients, respectively. Retrobulbar amphotericin injections used in 11.3% of subjects significantly affected the outcome (p-value=0.03, significant). Posaconazole step-down therapy was used in 72.5% of subjects (p-value=0.0005, significant). Surgical interventions were performed in 53 (85.48%) subjects (p-value=0.004, significant). Functional endoscopic sinus surgery was the most common (in 64.52% of subjects), followed by maxillectomy (20.97% of subjects) and craniotomy (17.7% of subjects). At the end of 12 weeks, 33.87% of patients died and 59.68% were alive; the rest (6.45%) were lost to follow-up. INTERPRETATION: The absence or late presentation of neurological symptoms led to a delayed diagnosis of cerebral mucormycosis. The presence of acute cerebral infarction indicated a worse prognosis. However, there was a significant influence of step-down posaconazole therapy, retrobulbar amphotericin injections, and surgical intervention on the prognosis of cerebral mucormycosis.

Full Remission of CAR-Deficient Tumors by DOTAP-Folate Liposome Encapsulation of Adenovirus.

Adenovirus (Ad)-based vectors have shown considerable promise for gene therapy. However, Ad requires the coxsackievirus and adenovirus receptor (CAR) to enter cells efficiently and low CAR expression is found in many human cancers, which hinder adenoviral gene therapies. Here, cationic 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP)-folate liposomes (Df) encapsulating replication-deficient Ad were synthesized, which showed improved transfection efficiency in various CAR-deficient cell lines, including epithelial and hematopoietic cell types. When encapsulating replication-competent oncolytic Ad (TAV255) in DOTAP-folate liposome (TAV255-Df), the adenoviral structural protein, hexon, was readily produced in CAR-deficient cells, and the tumor cell killing ability was 5× higher than that of the non-encapsulated Ad. In CAR-deficient CT26 colon carcinoma murine models, replication-competent TAV255-Df treatment of subcutaneous tumors by intratumoral injection resulted in 67% full tumor remission, prolonged survival, and anti-cancer immunity when mice were rechallenged with cancer cells with no further treatment. The preclinical data shows that DOTAP-folate liposomes could significantly enhance the transfection efficiency of Ad in CAR-deficient cells and, therefore, could be a feasible strategy for applications in cancer treatment.

Development of Adenovirus Containing Liposomes Produced by Extrusion vs. Homogenization: A Comparison for Scale-Up Purposes.

Adenovirus (Ad) is a widely studied viral vector for cancer therapy as it can be engineered to cause selective lysis of cancer cells. However, Ad delivery is limited in treating cancers that do not have coxsackievirus and adenovirus receptors (CAR). To overcome this challenge, Ad-encapsulated liposomes were developed that enhance the delivery of Ads and increase therapeutic efficacy. Cationic empty liposomes were manufactured first, to which an anionic Ad were added, which resulted in encapsulated Ad liposomes through charge interaction. Optimization of the liposome formula was carried out with series of formulation variables experiments using an extrusion process, which is ideal for laboratory-scale small batches. Later, the optimized formulation was manufactured with a homogenization technique-A high shear rotor-stator blending, that is ideal for large-scale manufacturing and is in compliance with Good Manufacturing Practices (GMP). Comparative in vitro transduction, physicochemical characterization, long-term storage stability at different temperature conditions, and in vivo animal studies were performed. Ad encapsulated liposomes transduced CAR deficient cells 100-fold more efficiently than the unencapsulated Ad (p ≤ 0.0001) in vitro, and 4-fold higher in tumors injected in nude mice in vivo. Both extrusion and homogenization performed similarly-with equivalent in vitro and in vivo transduction efficiencies, physicochemical characterization, and long-term storage stability. Thus, two Ad encapsulated liposomes preparation methods used herein, i.e., extrusion vs. homogenization were equivalent in terms of enhanced Ad performance and long-term storage stability; this will, hopefully, facilitate translation to the clinic.

Association of Early Beta Human Chorionic Gonadotropin With Ischemic Placental Disease in Singleton Pregnancies After In Vitro Fertilization.

OBJECTIVES: To evaluate whether an initial or two-day percent increase in serum beta-human chorionic gonadotropin (ßhCG) is associated with ischemic placental disease (IPD) in singleton pregnancies after autologous or donor IVF. STUDY DESIGN: This was a secondary analysis of a retrospective cohort study of deliveries linked to IVF cycles at a single academic tertiary hospital and infertility treatment center. We included all patients (≥18 years old) who had a singleton live birth or intrauterine fetal demise (IUFD) resulting from either autologous fresh (n=1,347), autologous frozen (n=454), or donor (n=253) IVF cycles. Main outcome reassures: The primary outcome was a composite outcome of IPD or IUFD due to placental insufficiency. IPDs included preeclampsia, placental abruption, and small for gestational age (SGA). RESULTS: Neither initial ßhCG nor two-day percent increases in ßhCG were associated with an increased risk of IPD for any type of IVF cycle. Initial and two-day percent increases in ßhCG were significantly higher when comparing frozen with fresh IVF and donor with autologous IVF (all P≤0.01). CONCLUSIONS: Among singleton autologous and donor IVF cycles, the initial and two-day percent increase in serum ßhCG were not associated with IPD or its components. However, significant ßhCG differences existed by cycle type and oocyte source.

The effect of interpregnancy interval on preterm birth and low birth weight in singleton pregnancies conceived without assistance or by infertility treatments.

OBJECTIVE: To determine the association of interpregnancy interval on perinatal outcomes and whether this was influenced by mode of conception. DESIGN: Retrospective cohort. SETTING: Centers for Disease Control and Prevention's natality national database. PATIENT(S): Patients who had an index singleton live birth with a preceding live birth. Index pregnancies from 2016 to 2019 were conceived with in vitro fertilization (IVF) (n = 32,829) or ovulation induction/intrauterine insemination (OI/IUI) (n = 23,016) or without assistance (n = 7,564,042). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The primary outcomes evaluated were preterm birth (<37 weeks) and low birth weight (<2,500 g). Multivariable logistic regression was performed to evaluate the association of interpregnancy intervals with perinatal outcomes stratified by mode of conception. Adjusted odds ratios and 95% confidence intervals (CIs) were presented. RESULT(S): Compared with the interpregnancy interval reference group of 12 to <18 months, a <12 month interpregnancy interval was associated with an increase in preterm birth (<37 weeks) for pregnancies conceived with OI/IUI or without assistance (aOR, 1.42; 95% CI, 1.16-1.74, and aOR, 1.14; 95% CI, 1.13-1.15, respectively), whereas IVF was not associated with an increase (aOR, 0.90; 95% CI, 0.77-1.04). A <12 month interpregnancy interval was associated with an increase in low birth weight for pregnancies conceived with IVF or OI/IUI or without assistance (aOR, 1.34; 95% CI, 1.09-1.64; aOR, 1.33; 95% CI, 1.01-1.76; and aOR, 1.26; 95% CI, 1.24-1.27, respectively). CONCLUSION(S): An interpregnancy interval of at least 12 months reduces adverse perinatal outcomes for pregnancies conceived with and without infertility treatment.

Impact of empathic physician contact on patient anxiety and distress during the waiting period after embryo transfer: a randomized controlled trial.

RESEARCH QUESTION: Can an empathic physician phone call in the interval between embryo transfer and first serum human chorionic gonadotrophin measurement decrease anxiety and distress amongst patients undergoing IVF? DESIGN: This was a randomized controlled trial at a single academically-affiliated fertility centre including patients aged 18-43 undergoing their first embryo transfer with autologous fresh or euploid cryopreserved embryos following preimplantation genetic testing for aneuploidies (frozen embryo transfer, FET/PGT-A). After embryo transfer, participants were randomized to a 5-minute scripted phone call (intervention) from a single physician 3-4 days after embryo transfer or to routine care. The primary and secondary outcomes included were change in State-Trait Anxiety Inventory (STAI) and Hospital Anxiety and Depression Scale (HADS) scores from the start of IVF stimulation to 8-9 days after embryo transfer, respectively. RESULTS: A total of 231 participants (164 fresh, 67 FET/PGT-A) were randomized to intervention (n = 116) or routine care (n = 115). While mean STAI and HADS scores increased in both groups, the intervention group experienced lower mean increases than the routine care group for both the STAI (3.3 [0.97] versus 7.8 [1.10], respectively; P = 0.002) and the HADS (0.3 [0.44] versus 2.4 [0.53], respectively; P = 0.003). Most participants in the intervention group found the call helpful (91.4%) and reported that it decreased distress and anxiety (81%). CONCLUSIONS: A brief empathic phone call from a physician during the waiting period resulted in significantly lower self-reported levels of patient anxiety and distress. As the intervention in this study averaged 5 min, implementing this in clinical practice would not be onerous and may ease the distress associated with the waiting period.

Endometrial compaction does not predict live birth in single euploid frozen embryo transfers: a prospective study.

STUDY QUESTION: Is there a relationship between endometrial compaction and live birth in euploid frozen embryo transfer (FET) cycles? SUMMARY ANSWER: Live birth rates (LBRs) were similar in both patients that demonstrated endometrial compaction or no compaction in single euploid FETs. WHAT IS KNOWN ALREADY: There has been increasing interest in the correlation between endometrial compaction and clinical outcomes but there has been conflicting evidence from prior investigations. STUDY DESIGN, SIZE, DURATION: This was a prospective observational study from 1 September 2020 to 9 April 2021. PARTICIPANTS/MATERIALS, SETTING, METHODS: This study was performed at a single, academically affiliated fertility center in which patients who had an autologous single euploid FET using a programmed or modified natural cycle protocol were included. All embryos had trophectoderm biopsy for preimplantation genetic testing for aneuploidy followed by vitrification at the blastocyst stage. Two ultrasound measurements of endometrial thickness (EMT) were obtained. The first measurement (T1) was measured transvaginally within 1 day of initiation of progesterone or ovulation trigger injection, and a second EMT (T2) was measured transabdominally at the time of embryo transfer (ET). The primary outcome (LBR) was based on the presence and proportion of compaction (percentage difference in EMT between T1 and T2). MAIN RESULTS AND THE ROLE OF CHANCE: Of the 186 participants included, 54%, 45%, 35%, 28% and 21% of women exhibited >0%, ≥5%, ≥10%, ≥15% and ≥20% endometrial compaction, respectively. Endometrial compaction was not predictive of live birth at any of the defined cutoffs. A sub-analysis stratified by FET protocol type (n = 89 programmed; n = 97 modified natural) showed similar results. LIMITATIONS, REASONS FOR CAUTION: There was the potential for measurement error in the recorded EMTs. The T2 measurement was performed transabdominally, which may cause potential measurement error, as it is generally accepted that transvaginal measurements of EMT are more accurate, though, any bias is expected to be non-differential. The sub-analysis performed looking at FET protocol type was underpowered and should be interpreted with caution. Our study, however, represents a pragmatic approach, as it allowed patients to avoid having to come in for an extra transvaginal ultrasound the day before or on the day of ET. WIDER IMPLICATIONS OF THE FINDINGS: Assessing endometrial compaction may lead to unnecessary cycle cancellation. However, further studies are needed to determine if routine screening for endometrial compaction would improve clinical outcomes. STUDY FUNDING/COMPETING INTEREST(S): No authors report conflicts of interest or disclosures. There was no study funding. TRIAL REGISTRATION NUMBER: NCT04330066.