United States

Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig disease, is a fatal neurodegenerative disease affecting motor neurons in the brain and spinal cord. Progressive muscle weakness, atrophy, and spasticity characterize the condition, which eventually leads to paralysis and respiratory failure. There is currently no cure for ALS, and the standard of care is supportive, with riluzole being one of the few FDA approved medications that has been shown to slightly slow disease progression along with Radicava (edaravone) and RELYVRIO (AMX0035) approved in 2022 with Qalsody (tofersen) being approved in 2023. With limited options for medications, the use of mesenchymal stem cells (MSCs) in the treatment of ALS is a new area of research in regenerative medicine. MSCs are multipotent stem cells that can differentiate into a variety of cell types, including neurons, and have immunomodulatory and anti-inflammatory properties, making them an appealing therapy for neurodegenerative diseases such as ALS. This review examines the safety and efficacy of MSC therapy for ALS in three Phase II randomized controlled trials. The trials involved administering MSCs via various routes, including intrathecal and intravenous, and assessing outcomes such as survival, disease progression, and quality of life. 


AMA Research Challenge 2023

Mesenchymal Stem Cell Therapy for Amyotrophic Lateral Sclerosis: A Narrative Review


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Background 
Benefits of early skin-to-skin contact (SSC) are widely documented, including improved breastfeeding outcomes. While promoting immediate SSC is standard practice for vaginal birth, it happens less often after cesarean birth.  It is not known how changes in hospital practices and staff shortages during the COVID-19 pandemic have influenced the practice of SSC in the operating room.  This study aims to identify the relationship between SSC after cesarean birth and breastfeeding and compare SSC rates before and during the COVID-19 pandemic. 
Methods 
This was a retrospective, cohort chart review. Sample was 244 subjects who had scheduled cesarean deliveries at term during April-October 2019 and April-October 2020. Primary outcome was exclusive breastfeeding on discharge. Secondary outcomes were time to initiate breastfeeding, exclusive breastfeeding at postpartum visit and rate of SSC in the OR in 2019 compared to 2020. 
Results 
SSC in the first 3 days after birth was associated with feeding type on discharge (p<0.001) and/or at the postpartum visit (p=0.04). The study did not identify a statistically significant association between location of SSC and feeding type either on discharge (p=0.55) or at the postpartum visit (p=0.55). Infants who had SSC in the OR had significantly earlier initiation of breastfeeding (p<0.001). There was an increase in SSC in the OR between 2019 and 2020 (27% and 39%, respectively).  
Conclusion 
SSC practices after cesarean birth are associated with breastfeeding outcomes. Knowledge of this relationship will be important for optimizing surrounding SSC practices and breastfeeding support in the future.

Skin-to-skin contact and breastfeeding after cesarean birth at UIHC, before and during the COVID-19 pandemic

Background: Sonographic measurement of foetal biparietal diameter is a
well-accepted predictor of gestational age. However, there is a high variability
in the calculated gestational age which increases as pregnancy progresses with a
maximum difference approximating 3.6 weeks in the third trimester. Conditions
like oligohydramnios can alter the shape of the foetal skull, affect the BPD and
increase variability. The present study is being undertaken to measure the
transverse cerebellar diameter (TCD) to validate it as an additional
morphological measurement of foetal growth with less variability.
The cerebellum and posterior fossa are aligned perpendicular to the plane of
maximum extrinsic compression. Hence they can withstand deformation by
extrinsic pressure than the parietal bones and can be a more accurate parameter
for determining gestational age.
Methods: A cross-sectional study was done in 100 healthy women with
uncomplicated pregnancy between the 28th week of gestation and 40th week of
gestation over three years in outpatient and in-patient sections of Obstetrics and
Gynaecology Department of SRM Hospital and Research Institute,
Kattankulathur, Chennai. This study was undertaken to determine a correlation
between the transverse cerebellar diameter and the gestational age as
determined by the last menstrual period and other sonographic parameters like
biparietal diameter and femur length. After satisfying the inclusion and
exclusion criteria, Transabdominal ultrasonography was performed with the
patient in a supine position. The Pearson Correlation technique was used to test
the direction and strength of the relationship between gestational age obtained
using transverse cerebellar diameter vs individual parameters such as biparietal
diameter and femoral length.
Results: A scatter diagram showing the correlation and regression analysis of
the Gestational age with BPD in the third trimester. Here TCD is correlated with
BPDby87.1 %. A scatter diagram showing the correlation and regression
analysis of the TCD with FL in the third trimester. Here TCD is correlated with
FL by 93.0 %
Conclusion: Obstetric sonography was performed in 100 pregnant women with
uncomplicated pregnancy with known LMP, previous history of normal
menstrual cycle, and no exclusion criteria were included in the study. Foetal
biometry evaluated includes BPD, FL, and TCD. The nomogram of the TCD
shows that there is a linear relationship between cerebellar growth and
gestational age. So TCD can be used as a reliable parameter for determining
gestational age

 Accuracy of transcerebellar diameter in estimation of gestational age in third trimester and its comparison with conventional parameters such as biparietal diameter and femur length

Introduction
Trauma complicates 1 in 12 pregnancies and is the leading cause of mortality outside of obstetric-related complications. Guidelines for trauma activation in pregnancy differ from non-pregnant populations but are not universally established. This study aims to investigate under or overtriage of our pregnant patient population according to our established trauma triage criteria.
Methods
A retrospective study including all patients with pregnancy and trauma ICD-10 codes between January 2017-December 2020 at a level 1 trauma center was included. Patient demographics, vitals, injuries, service involvement during admission, gestational age, and obstetric and medical history were collected and compared to our hospital’s trauma triage criteria to evaluate undertriage in this patient population.
Results
330 patients were identified based on inclusion criteria. Trauma evaluation only occurred in 13.0% of patients and 30.9% of patients received obstetric (OB) evaluation. According to our institutional criteria, 55.8% of all pregnant patients had a missed trauma evaluation. 87.2% (n=130/149) of patients ≥20 weeks had a missed trauma evaluation (Fig. 1). For patients presenting directly to the trauma bay, patients ≥20 weeks received OB evaluation 100% (n=11) of the time, and patients <20 weeks received OB evaluation only 53.9% (n=7/13) of the time.
Conclusion
Pregnant patients are a vulnerable population, and thus, it is essential to triage these patients based on OB-specific criteria. This study has revealed that most OB patients are undertriaged according to our institution's criteria, prompting further investigation to understand barriers to appropriate triage.

Trauma Trends and Outcomes in Obstetrical Patients at a Level 1 Trauma Center

Background
Pregnant women were one of the most vulnerable populations during the Coronavirus Disease 2019 (COVID-19) pandemic. Understanding how the pandemic influenced prenatal care utilization and birth outcomes of pregnant populations is essential to guiding disaster preparedness in the face of future global threats. We sought to evaluate the COVID-19 pandemic’s influence on the adequacy of prenatal care and birth outcomes.

Methods
Retrospective cohort study compared prenatal care adequacy, diagnostic testing, and gestational age of 481 patients seen at an urban medical center in New York City during the pandemic (October 1, 2020 and October 14, 2020), and in the corresponding pre-pandemic period (October 1, 2019 and October 14, 2019) using student t-test, Mann-Whitney, and chi-squared tests.

Results
Patients seen during the pandemic were more likely to receive Adequate Prenatal Care (OR 2.634 95%CI 1.672-4.184 p < 0.001) than pre-pandemic patients (OR 0.385 95% CI 0.244-0.606 p < 0.001). Adequate Prenatal Care (OR 0.102 95%CI 0.014-0.763 p = 0.005) was negatively associated with early preterm pregnancy (32-36 weeks). There were no statistically significant differences in gestational age between the pre-pandemic and pandemic cohorts (Moderate Preterm 32-36 weeks OR 1.145 95%CI 0.532-2.465 p=0.845, Early Term 37-38 weeks OR 1.049 95%CI 0.658-1.671 p=0.905, Full Term OR 1.044 95% CI 0.689-1.581 p=0.916). 

Conclusion
Though the pandemic imposed unprecedented stresses upon expectant mothers, patients had significantly greater likelihoods of receiving adequate prenatal care during the pandemic, which may be attributed to the expansion of telehealth services and increased health awareness. Despite this increase in prenatal care adequacy, the pandemic had no statistically significant influence on preterm birth rates.

Improving Prenatal Care Adequacy in Urban Settings: Lessons from the COVID 2019 Pandemic

Background: Prior studies demonstrate that chronic prenatal opioid exposure leads to an increased risk for preterm labor and fetal growth restriction, both conditions associated with placenta insufficiency. Current literature also suggests that chronic prenatal opioid exposure negatively impacts the placenta (and fetus) during a critical developmental period where unyielding foundational processes for organ growth are initiated. Not only is there evidence of abnormal biochemical signaling between the placenta and fetus, but there is also histological evidence of chronic hypoxia in placentas chronically exposed to opioids. In a worsening opioid epidemic where identifying avenues for future therapeutics has become critical, the placenta may be an ideal therapeutic target for improving fetal health outcomes related to exposure. The goal of this study was to investigate histological differences in human placental tissue following chronic prenatal opioid exposure.

Methods: Placental tissue was collected from 7 opioid-exposed and 17 unexposed placentas from full-term pregnancies. Analyses were completed for 7 unexposed, control placentas by matching age and smoking history to exposed placentas. All participants in the opioid-exposed group were exclusively taking buprenorphine at some point during their third trimesters. Placental tissue samples were fixed in neutral buffered, 10% formalin, embedded in paraffin wax, and stained with hematoxylin and eosin prior to blinded histopathological analysis by an experienced pathologist. A generalized linear mixed model with a binomial outcome, paired t-tests, and linear mixed effects models were utilized to measure the frequency of a grade 2 or higher score (grade 3 or higher, villous morphology), total grade, or average grade.

Results: No statistically significant differences were observed in vascular pathology and inflammation between the opioid-exposed group and their respective matched controls. The control group placentas were found to exhibit significantly higher frequencies of grade 3, 4 or 5 villous morphology compared to the opioid-exposed placental tissue. When villous morphology was measured by total and average grade, no statistically significant differences were appreciated. 

Conclusion: The findings from this study may suggest that chronic opioid exposure, specifically chronic exposure to the partial opioid agonist buprenorphine, may not have unfavorable histopathological consequences as compared to unexposed placentas. The findings of this study may be limited by small sample size and an inability to control for other substances being used (including tobacco and illicit drugs) in the exposed group throughout pregnancy. Further investigation of microvascular changes as well as signaling changes in the placenta following chronic prenatal opioid exposure is warranted.

Histopathology of placental tissue after chronic opioid exposure

Background
Vaginal agenesis (VA) refers to the congenital absence of a vaginal canal often linked with Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome. Current VA treatments include mechanical dilation and surgical vaginoplasty. Our vaginal expansion sleeve (VES) is a novel, transiently implanted device which lengthens the vaginal canal over time and is less complex and invasive than surgery or conventional dilation therapy which may improve patient compliance. Our study evaluated histologic effects of VES on rat vaginal tissue following VA.

Methods
Novel VES were made using a proprietary woven cylindrical material with helicoid trusses and flat resin caps. VES were used at 25-30mm in length depending on initial vaginal canal lengths and all VES pre-contracted to 50% of their original length. VES were then inserted and sutured into the vaginal canals of Sprague-Dawley rats (n=6) and allowed to spontaneously re-expand post-deployment. After one week, VES were removed and new vaginal lengths were measured. Rat vaginas were harvested en-bloc for histologic analysis. Test (n=6) and control (n=4) formalin-fixed paraffin-embedded tissues were stained with hematoxylin and eosin (H&E), Masson’s trichrome, and anti-Desmin immunochemical stain and evaluated.

Results
In 7days, mean vaginal canal lengths increased from 20.0 ± 2.4 mm to 23.8 ± 1.2 mm post-VES (n=6, p <.001), a 19% increase. H&E staining revealed increased submucosal eosinophilic inflammation in 5:6 of samples compared to 1:4 control tissues with an average 30.2 eosinophils per HPF (range: 16 - 38; median: 35). The test tissues also showed increased scattered neutrophils and lymphocytes in the mucosa and submucosa, with one test tissue having the longest VES (30mm) containing lymphocytic and neutrophilic inflammation. Desmin immunostaining and Masson’s trichrome staining both revealed a thinner muscularis with more infiltrative fibrous tissue between muscle fibers in the test tissues compared to control tissues.

Conclusion
VESs achieved significant vaginal lengthening. A positive correlation was observed between the VES length (and therefore tension generated in the vagina) and the degree of inflammation. The eosinophilia observed in the test tissues may indicate a localized, specific immune reaction to the VES device. The Desmin immunostain and Masson’s trichrome stain is consistent with muscularis remodeling. Future studies with longer durations of VES placement as well as serial implants with VESs of increasing lengths can inform longer-term remodeling of test tissues and help further characterize immune response associated with VES.

Histologic Changes in Rat Vaginal Tissue Following Vaginal Expansion Sleeve (VES) Implantation: Implications for Vaginal Agenesis Treatment

Background
Premature ovarian failure, whether occurring spontaneously or iatrogenically, especially as a result from chemotherapy, is a challenging clinical problem in Reproductive Endocrinology and Infertility and Oncology. These patients have no autologous fertility-restoration options available if preemptive egg or embryo freezing was not successfully completed. Lack of endogenous hormone production has sequelae beyond reproduction, including accelerated bone loss, increased risk of cardiovascular disease, and sexual dysfunction. While hormone replacement therapies exist, long-term outcomes from such treatments, especially when initiated at a young age, remain unclear. These issues are heightened in cancer survivors, who have lower baseline fertility rates and success with assisted reproduction.
Methods
A methodology for the creation of oocytes via reprogrammed granulosa cells was first performed in mouse and, to the greatest extent possible, recapitulated in human cells. Granulosa cells (GCs) were reprogrammed to generate induced pluripotent stem cells (IPSCs) as previously described in our lab. Human GCs and follicular fluid were obtained from the IVF lab after oocyte removal during egg retrieval procedures. Cells were labeled with GFP and differentiated into ovarian lineages using an oocyte derivation media containing follicular fluid. Stem cell and differentiated cell status was verified via RT-PCR, immunocytochemistry, alkaline-phosphatase reaction, steroidogenic activity, and the formation of embryoid bodies and teratomas. Mouse GFP-labeled differentiated IPSCs were orthotopically implanted into one ovary of subfertile immunocompromised mice which also had chemotherapeutically-induced ovarian failure to assess for the restoration of hormone production and fertility.
Results
Differentiated IPSCs expressed ovarian markers (i.e. AMHR2, ZP1) and were able to produce physiologically relevant concentrations of the reproductive steroid hormones (i.e. estradiol/progesterone) in vitro. Interestingly, the addition of follicular fluid increased the steroidogenic potential of the cells in mice. Mice treated with alkylating chemotherapy to induce ovarian failure had ovarian follicular atresia and breast atrophy, which was reversed within 72 hours of transplanting terminally differentiated GFP-IPSCs into the thighs or ovaries of these mice. In subfertile nude mice, the orthotopic implantation of terminally differentiated IPSCs enhanced fertility, resulting stem cell-derived neogametogenesis and delivery of F1 and F2 litters with GFP expression.
Conclusion
New autologous methods of restoring fertility and ovarian function would be indispensable for patients with prematurity ovarian insufficiency or failure. Our work demonstrates that other populations of cells within the body may be reprogrammed for the purpose of endocrine health and fertility restoration in such patients.

The Generation of Stem Cell-Derived Functional Oocytes from Reprogrammed Granulosa Cells

Background: Cardiovascular disease (CVD) affects 1-4% of pregnancies in the U.S. and is the primary contributor to morbidity and mortality in pregnancy and post-partum. While it has been established that adverse pregnancy outcomes (APOs) increase future maternal CVD risk, the factors predicting these pregnancy complications are less studied. Our primary objective is to report preliminary data from our cardio-obstetrics registry on the association between pre-conception cardiovascular risk factor burden and APO development. Given the relative sparsity of cardio-obstetrics patient data, we also aim to contribute patient demographics.

Methods: Utilizing retrospective chart review, we created a registry of patients evaluated at USF’s cardio-obstetrics program October 7, 2021-November 1, 2022. Charts were queried for demographics, pre-conception risk factors, and maternal-fetal outcomes. Risk factors included BMI>25 kg/m2, chronic hypertension, hyperlipidemia, pre-existing diabetes, tobacco use, sleep apnea, chronic kidney disease, autoimmune disease, advanced maternal age, and history of a prior APO. APOs were defined as intrauterine growth restriction (IUGR), hypertensive disorder of pregnancy (HDP), and pre-term birth (delivery <37 weeks). Statistical analysis included chi-square test and Fisher’s exact test for categorical variables and Mann-Whitney U test for continuous variables.

Results: Our analysis included 63 women, most commonly presenting with valvular or structural heart disease (33.3%), cardiomyopathy (28.6%), and arrythmias (15.9%). Throughout pregnancy and post-partum, 42 (66.7%) women did not experience any APO, while 21 (33.3%) did; 19 (30.2%) developed an HDP, 3 (4.8%) experienced IUGR, and 12 (19.0%) delivered pre-term. Race, ethnicity, age, gravidity, parity, gestational age at first cardio-obstetrics visit, and individual risk factors were not significantly associated with APO development. Analysis of risk factor burden showed the number of risk factors a woman had pre-conception was not a statistically significant predictor APO development (p=0.139). While the risk factor burden did not affect the overall incidence of APOs, patients who gave birth pre-term did have a significantly higher number of risk factors (p<0.001; 3.08 ± 1.00 pre-term, 1.69 ± 1.19 not pre-term), as did patients with chronic hypertension with superimposed HDP (p<0.001; 3.43 ± 0.79 with, 1.77 ± 1.21 without). 

Conclusion: Cardiovascular risk factor burden was not associated with APO development in pregnant women with CVD. Women who deliver pre-term may have a higher risk factor burden than those who deliver at term. Since pre-term birth is associated with future CVD in women independent of its cause, optimization of preconception cardiovascular health could help mitigate these risks in an already vulnerable high-risk population.

Cardiovascular Risk Factor Burden and Adverse Pregnancy Outcomes in Women with Cardiovascular Disease


Background:

The two main classes of AMTs commercially available today are “cryopreserved” and “dehydrated.”

Many studies have indicated that the process of cryopreservation is effective at maintaining both the quantity and activity of biological signaling proteins found within the amniotic tissue. One notable drawback of cryopreserved amniotic membranes is that they carry a higher monetary cost due to their stringent production and storage requirements.

Dehydrated amniotic membranes are a cheaper alternative to their cryopreserved counterparts. This is primarily because they have simpler storage requirements, as they can be kept at room temperature. However, studies have also shown that dehydrated amniotic membranes are less effective at maintaining the availability and activity of important biological factors that influence healing and tissue regeneration. Yet, it remains unclear if these findings have any significant real-world implications in a clinical setting. Accordingly, our study seeks to identify and compare the benefits and shortcomings of each type of membrane. 

Methods: 

We completed a retrospective, non-inferiority trial involving 36 patients who formed 2 populations. Group 1 received a cryopreserved membrane while Group 2 received a dehydrated membrane. The duration of therapy was 1 week. We recorded each patient's indications, number of amniotic membrane transplants (AMTs), adjunct medications, tolerability, visual acuity, and ocular pressure pre/post treatment. A positive outcome at the 1-month post-AMT visit was defined as improvement in ≥3 symptoms of eye irritation, resolution of primary indication for AMT, improvement in visual acuity, and improvement in intraocular pressure. If the criteria was not met, the outcome was considered to be negative. This trial was non-randomized nor blinded.


Results:
51 AMTs from 36 patients were included. At both the 1 week and 1 month interval, patients who received a cryopreserved amniotic membrane transplant (CAMT) self-reported a greater number of side-effects when compared to patients who received a dehydrated membrane (DAMT). Those who received a CAMT also had greater vision improvement and a higher self-reported feeling of wellness at both intervals when compared to patients who received a DAMT [P =.03]. Patients who received a DAMT were less likely to require repeated treatments [P = .001]. 

Conclusion:
Cryopreserved membranes are currently more expensive than dehydrated membranes. These cost disparities become amplified given that our data suggests a higher re-treatment rate in the Group 1. Despite these concerns, CAMTs may be viewed as a more effective treatment since patients in this cohort were more likely to have a positive outcome.


Comparing patient tolerability of cryopreserved and dehydrated amniotic membrane transplantations for managing corneal disease

Introduction: This study identifies retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA) patients at an inherited retinal disease (IRD) clinic that qualify for ongoing or FDA-approved adeno-associated virus (AAV) gene-replacement therapies. The goal is to demonstrate the benefits of genetic testing at the initial evaluation.

Method: A database for RP and LCA patients was curated and clinicaltrials.gov was used to search all ongoing or approved gene-replacement therapies between 1 January 2022 – 1 January 2023. Patients were evaluated for qualification based on the inclusion/exclusion criteria set by each trial.

Results: 199 RP and 31 LCA patients were included in the study. Our team identified six AAV gene-replacement therapy clinical trials and the FDA-approved Luxturna®. One hundred fifty-five patients underwent genetic testing, and 89 patients had a pathogenic variant identified. A total of 15 patients qualified for one of the proposed trials. Three patients had a biallelic RPE65 mutation, and two of them qualified for Luxturna®. All 11 patients with an RPGR mutation qualified for one of the three clinical trials that focused on this gene. Three patients had a c.2991+1655A>G mutation in CEP290 and two of them qualified one of two clinical trials for this gene.

Conclusion: Overall, ~10% of patients who had genetic testing qualified for one of the reviewed therapies. A total of 15 patients qualified for an AAV gene-replacement therapy. This study highlights the importance of promoting genetic testing for IRD patients, the need for earlier disease evaluation, and the value of continual monitoring of disease progression.


Next from AMA Research Challenge 2023

Skin-to-skin contact and breastfeeding after cesarean birth at UIHC, before and during the COVID-19 pandemic