Altered Inflammatory State and Mitochondrial Function Identified by Transcriptomics in Paediatric Congenital Heart Patients Prior to Surgical Repair.

Congenital heart disease (CHD) remains the most common birth defect, with surgical intervention required in complex cases. Right ventricle (RV) function is known to be a major predictor of sustained cardiac health in these patients; thus, by elucidating the divergent profiles between CHD and the control through tissue analysis, this study aims to identify new avenues of investigation into the mechanisms surrounding reduced RV function. Transcriptomic profiling, in-silico deconvolution and functional network analysis were conducted on RV biopsies, identifying an increase in the mitochondrial dysfunction genes RPPH1 and RMPR (padj = 4.67 × 10-132, 2.23 × 10-107), the cytotoxic T-cell markers CD8a, LAGE3 and CD49a (p = 0.0006, p < 0.0001, and p = 0.0118) and proinflammatory caspase-1 (p = 0.0055) in CHD. Gene-set enrichment identified mitochondrial dysfunctional pathways, predominately changes within oxidative phosphorylation processes. The negative regulation of mitochondrial functions and metabolism was identified in the network analysis, with dysregulation of the mitochondrial complex formation. A histological analysis confirmed an increase in cellular bodies in the CHD RV tissue and positive staining for both CD45 and CD8, which was absent in the control. The deconvolution of bulk RNAseq data suggests a reduction in CD4+ T cells (p = 0.0067) and an increase in CD8+ T cells (p = 0.0223). The network analysis identified positive regulation of the immune system and cytokine signalling clusters in the inflammation functional network, as there were lymphocyte activation and leukocyte differentiation. Utilising RV tissue from paediatric patients undergoing CHD cardiac surgery, this study identifies dysfunctional mitochondrial pathways and an increase in inflammatory T-cell presence prior to reparative surgery.

Growth capacity of a Wharton's Jelly derived mesenchymal stromal cells tissue engineered vascular graft used for main pulmonary artery reconstruction in piglets.

Background: Surgical treatment of congenital heart defects affecting the right ventricular outflow tract (RVOT) often requires complex reconstruction and multiple reoperations due to structural degeneration and lack of growth of currently available materials. Hence, alternative approaches for RVOT reconstruction, which meet the requirements of biocompatibility and long-term durability of an ideal scaffold, are needed. Through this full scale pre-clinical study, we demonstrated the growth capacity of a Wharton's Jelly derived mesenchymal stromal cells (WJ-MSC) tissue engineered vascular graft used in reconstructing the main pulmonary artery in piglets, providing proof of biocompatibility and efficacy. Methods: Sixteen four-week-old Landrace pigs were randomized to undergo supravalvar Main Pulmonary Artery (MPA) replacement with either unseeded or WJ-MSCs-seeded Small Intestinal Submucosa-derived grafts. Animals were followed up for 6 months by clinical examinations and cardiac imaging. At termination, sections of MPAs were assessed by macroscopic inspection, histology and fluorescent immunohistochemistry. Results: Data collected at 6 months follow up showed no sign of graft thrombosis or calcification. The explanted main pulmonary arteries demonstrated a significantly higher degree of cellular organization and elastin content in the WJ-MSCs seeded grafts compared to the acellular counterparts. Transthoracic echocardiography and cardiovascular magnetic resonance confirmed the superior growth and remodelling of the WJ-MSCs seeded conduit compared to the unseeded. Conclusion: Our findings indicate that the addition of WJ-MSCs to the acellular scaffold can upgrade the material, converting it into a biologically active tissue, with the potential to grow, repair and remodel the RVOT.

Protocol to decellularize porcine right ventricular outflow tracts using a 3D printed flow chamber.

Surgical treatment of pediatric congenital heart disease with tissue grafts is a lifesaving intervention. Decellularization to reduce immunogenicity of tissue grafts is an increasingly popular alternative to glutaraldehyde fixation. Here, we present a protocol to decellularize porcine right ventricular outflow tracts using a 3D printed flow chamber. We describe steps for 3D printing the flow rig, preparing porcine tissue, and using the flow rig to utilize shear forces for decellularization. We then detail procedures for characterizing the acellular scaffold. For complete details on the use and execution of this protocol, please refer to Vafaee et al.1.

Microarray evidence that 8-cell human embryos express some hormone family members including oxytocin.

OBJECTIVE: This study is to discover hormone pathways active in early cleaving human embryos. METHODS: A list of 152 hormones and receptors were compiled to query the microarray database of mRNAs in 8-cell human embryos, two lines of human embryonic stem cells plus human fibroblasts before and after induced pluripotency. RESULTS: Over half of the 152 hormones and receptors were silent on the arrays of all cell types, and more were detected at high or moderate levels on the 8-cell arrays than on the pluripotent cell or fibroblast arrays. Eight hormone family genes were uniquely detected at least 22-fold higher on the 8-cell arrays than the stem cell arrays: AVPI1, CCK, CORT, FSTL4, GIP, GPHA2, OXT, and PPY suggesting novel roles for these proteins in early development. Oxytocin was detected by pilot immunoassay in culture media collected from Day 3 embryos. Robust detection of CRHR1 and EPOR suggests the 8-cell embryo may be responsive to maternal CRH and EPO. The over-expression of POMC and GHITM suggests POMP peptide products may have undiscovered roles in early development and GHITM may contribute to mitochondrial remodeling. Under-detected on the 8-cell arrays at least tenfold were two key enzymes in steroid biosynthesis, DHCR24 and FDPS. CONCLUSIONS: The 8-cell human embryo may be secreting oxytocin, which could stimulate its own progress down the fallopian tube as well as play a role in early neural precursor development. The 8-cell embryo does not synthesize reproductive steroid hormones. As previously reported for growth factor families, the early embryo over-expresses more hormones than hormone receptors.

Graft rejection in paediatric congenital heart disease.

Congenital heart disease (CHD) affects around 1.35 million neonates worldwide per annum, and surgical repair is necessary in approximately 25% of cases. Xenografts, usually of bovine or porcine origin, are often used for the surgical reconstruction. These xenografts elicit an immune response due to significant immunological incompatibilities between host and donor. Current techniques to dampen the initial hyperacute rejection response involve aldehyde fixation to crosslink xenoantigens, such as galactose-α1,3-galactose and N-glycolylneuraminic acid. While this temporarily masks the epitopes, aldehyde fixation is a suboptimal solution, degrading over time, resulting in cytotoxicity and rejection. The immune response to foreign tissue eventually leads to chronic inflammation and subsequent graft failure, necessitating reintervention to replace the defective bioprosthetic. Decellularisation to remove immunoincompatible material has been suggested as an alternative to fixation and may prove a superior solution. However, incomplete decellularisation poses a significant challenge, causing a substantial immune rejection response and subsequent graft rejection. This review discusses commercially available grafts used in surgical paediatric CHD intervention, looking specifically at bovine jugular vein conduits as a substitute to cryopreserved homografts, as well as decellularised alternatives to the aldehyde-fixed graft. Mechanisms of biological prosthesis rejection are explored, including the signalling cascades of the innate and adaptive immune response. Lastly, emerging strategies of intervention are examined, including the use of tissue from genetically modified pigs, enhanced crosslinking and decellularisation techniques, and augmentation of grafts through in vitro recellularisation or functionalisation with human surface proteins.

Feasibility and Acceptability of Using Ecological Momentary Assessment to Evaluate Alcohol Use with American Indian Women.

BACKGROUND: Ecological momentary assessments (EMA) are one way to collect timely and accurate alcohol use data, as they involve signaling participants via cell phones to report on daily behaviors in real-time and in a participant's natural environment. EMA has never been used with American Indian populations to evaluate alcohol consumption. The purpose of this project was to determine the feasibility and acceptability of EMA for American Indian women. METHODS: Eligible participants were American Indian women between the ages of 18 and 44 who were not pregnant and had consumed more than one drink within the past month. All participants received a TracFone and weekly automated messages. Self-reported measures of daily quantity and frequency of alcohol consumption, alcohol type, and context were assessed once per week for four weeks. Baseline measurements also included the Drinking Motives Questionnaire-Revised (DMQ-R) and the Interpersonal Support Evaluation List (ISEL). RESULTS: Fifteen participants were enrolled in the study. All but one participant completed all data collection time points, and drinking patterns were consistent across the study period. A total of 420 records were completed across 86 drinking days and 334 non-drinking days. Participants reported drinking an average of 5.7 days over the 30-day period and typically consumed 3.99 drinks per drinking occasion. Sixty-six percent of participants met gender-specific cut-points for heavy episodic drinking, with an average of 2.46 binge drinking occasions across the four week study period. CONCLUSIONS: This proof-of-concept project showed that EMA was both feasible and acceptable for collecting alcohol data from American Indian women. Additional studies are necessary to fully implement EMA with American Indian women to better understand the drinking motives, contexts, patterns, and risk factors in this population.

Biological Scaffolds for Congenital Heart Disease.

Congenital heart disease (CHD) is the most predominant birth defect and can require several invasive surgeries throughout childhood. The absence of materials with growth and remodelling potential is a limitation of currently used prosthetics in cardiovascular surgery, as well as their susceptibility to calcification. The field of tissue engineering has emerged as a regenerative medicine approach aiming to develop durable scaffolds possessing the ability to grow and remodel upon implantation into the defective hearts of babies and children with CHD. Though tissue engineering has produced several synthetic scaffolds, most of them failed to be successfully translated in this life-endangering clinical scenario, and currently, biological scaffolds are the most extensively used. This review aims to thoroughly summarise the existing biological scaffolds for the treatment of paediatric CHD, categorised as homografts and xenografts, and present the preclinical and clinical studies. Fixation as well as techniques of decellularisation will be reported, highlighting the importance of these approaches for the successful implantation of biological scaffolds that avoid prosthetic rejection. Additionally, cardiac scaffolds for paediatric CHD can be implanted as acellular prostheses, or recellularised before implantation, and cellularisation techniques will be extensively discussed.

West Nile virus in a patient with Good's syndrome.

We describe the association between thymoma and hypogammaglobulinemia (Good's Syndrome) and a fulminant, seronegative West Nile Virus neuroinvasive infection confirmed by nucleic acid amplification. Diagnostic difficulties are emphasized and historical minutiae are highlighted.

Voice Therapy Expectations for Injured Singers.

OBJECTIVES/HYPOTHESIS: Voice therapy is a mainstay treatment modality in the management of phonotrauma in singers. However, the typical duration of therapy an injured singer undergoes is unknown. The primary aims of the study were to determine (1) the number of therapy sessions preceding a decision for surgery and (2) the number of sessions and length of time to achieve improvement in singers who did not undergo surgery. Whether specific singer factors were associated with the length of therapy was also investigated. STUDY DESIGN: Retrospective. METHODS: Records of singers with phonotraumatic vocal fold lesions seen over a 9-year period at a tertiary care voice center were reviewed. RESULTS: Sixty singers who underwent surgery and 183 singers who did not undergo surgery were included in the final analysis. In nearly ¾ of the surgical patients, five or fewer voice therapy sessions were completed prior to the decision for surgery. Singers who did not undergo surgery required on average 3-4 sessions before noting improvement. Over 60% of the non-surgical singers improved within 3 months and 84% were judged to be improved by 6 months. Lesion type, professional/amateur status, formal voice training, and having a current voice teacher/coach were not associated with the length of voice therapy. CONCLUSIONS: The length of voice therapy prior to decision for surgery was limited, and so was the length of therapy leading to initial improvement in singers who did not require surgery. These findings provide a framework for voice therapy expectations and could be reassuring for this unique population.

Adaptations of an RCT during COVID: Case Study in one Rural American Indian Community.

The COVID-19 pandemic is global in nature but especially threatens American Indian and Alaska Native (AI/AN) communities due to pre-existing conditions and social determinants of health. Because of the higher risk to AI/AN communities, many tribal nations have been proactive in their policies to keep the virus at bay, including travel restrictions and lockdowns. This affected tribal programs as well as collaborative research projects. One project impacted is the Native CHOICES project, an ongoing randomized controlled trial with an AI/AN community that is focused on the prevention of alcohol-exposed pregnancies. Originally designed to be conducted via in-person motivational interviewing sessions, COVID-19 restrictions precluded the intervention from being delivered in-person as it was designed. The study team received valuable input from the project's Community Advisory Board (CAB) and community-based staff to establish a feasible and acceptable way of conducting the intervention while respecting tribally-enacted COVID-19 restrictions. The goal of this brief report is to outline not just the process to adapting to COVID-19 but also to provide recommendations for future public health programs, including the ongoing need to consider gaps in access affecting resource-poor settings.

Virtual Compared With In-Clinic Transvaginal Ultrasonography for Ovarian Reserve Assessment.

OBJECTIVE: To evaluate noninferiority of virtual transvaginal ultrasonography compared with in-clinic ultrasonography for ovarian reserve assessment. METHODS: We conducted a single-site, head-to-head crossover trial. Participants performed self-administered virtual transvaginal ultrasonography at home, guided by a remote-certified ultrasound technologist, then underwent transvaginal ultrasonography in-clinic with another ultrasound technologist. Participants were women in the greater Boston area interested in evaluating ovarian reserve and recruited through social media, health care referrals, and professional networks. The uterus and ovaries were captured in sagittal and transverse views. These randomized recordings were reviewed by two or three independent, blinded reproductive endocrinologists. The primary outcome was noninferiority of the rate of clinical quality imaging produced at home compared with in clinic. Sample size was selected for greater than 90% power, given the 18% noninferiority margin. Secondary outcomes included antral follicle count equivalency and net promoter score superiority. RESULTS: Fifty-six women were enrolled from December 2020 to May 2021. Participants varied in age (19-35 years), BMI (19.5-33.9), and occupation. Ninety-six percent of virtual and 98% of in-clinic images met "clinical quality." The difference of -2.4% (97.5% CI lower bound -5.5%) was within the noninferiority margin (18%). Antral follicle counts were equivalent across settings, with a difference in follicles (0.23, 95% CI -0.36 to 0.82) within the equivalence margin (2.65). Virtual examinations had superior net promoter scores (58.1 points, 97.5% CI of difference 37.3-79.0, P<.01), indicating greater satisfaction with the virtual experience. CONCLUSION: Virtual transvaginal ultrasonography remotely guided by an ultrasonography technologist is noninferior to in-clinic transvaginal ultrasonography for producing clinical quality images and is equivalent for estimating antral follicle count. Virtual transvaginal ultrasonography had superior patient satisfaction and has potential to significantly expand patient access to fertility care. FUNDING SOURCE: This study was sponsored by Turtle Health. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT04687189.

The State of Web Accessibility for People with Cognitive Disabilities: A Rapid Evidence Assessment.

Increased digitisation of day-to-day activities was occurring prior to the COVID-19 pandemic. The pandemic only accelerated the virtual shift, making web accessibility an urgent issue, especially for marginalised populations. Despite decades of work to develop, refine, and implement web accessibility standards, people with cognitive disabilities regularly experience many barriers to web accessibility. To inform ongoing work to improve web accessibility for people with cognitive disabilities, a systematic review was conducted. The main question guiding this review is: what are the state-of-the-art of interventions that support web accessibility for citizens, 9 years of age and up, living with cognitive impairment? A set of 50 search strings were entered into three academic databases: SCOPUS, ProQuest, and Web of Science. Systematic screening procedures narrowed the search returns to a total of 45 included papers. A data analysis revealed themes associated with the lived experiences of people with cognitive disabilities, tools for improving web accessibility, and methodological best practices for involving people with cognitive disabilities in research. These findings have immediate implications for ongoing research and the development of meaningful solutions to the problem of web accessibility for people with cognitive disabilities.

A Pilot Randomized Control Trial to Assess the Impact of Lavender on Anxiety and Comfort After Cesarean Birth and the Barriers Encountered.

PURPOSE: This study aimed to assess the effect of lavender aromatherapy on anxiety and comfort after cesarean birth. STUDY DESIGN: Randomized control trial. METHODS: Forty-eight patients who had a cesarean birth were asked to complete the six-item State and Trait Anxiety (STAI-6) score to assess their level of anxiety pre- and postapplication of either lavender aromatherapy or placebo during their inpatient postpartum stay. Their comfort and pain levels pre- and postadministration were assessed, and differences between groups were analyzed. Results: There was no difference in postintervention STAI-6 scores between the aromatherapy and placebo groups (p = .56). Women who received the lavender aromatab® had significantly (p = .037) higher self-reported levels of comfort (M 2.6 SD .82) when compared with those who received placebo (M 2.0 SD 1.0). CLINICAL IMPLICATIONS: Many women use aromatherapy at home to promote comfort and relaxation. Women feel lavender aromatherapy improves their comfort in the hospital setting after cesarean birth. Clinicians should consider ways to safely use aromatherapy as one option to promote postoperative cesarean birth care.

Placental pathology of term singleton live births conceived with fresh embryo transfer compared with those conceived without assisted reproductive technology.

OBJECTIVE: To compare placental pathology from term singleton live births conceived with fresh embryo transfer vs. those conceived without assisted reproductive technology (ART). DESIGN: Retrospective cohort study. SETTING: Academic fertility center. PATIENT(S): Women with a term singleton live birth who conceived after fresh autologous in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) cycles (ART group) and those who conceived without ART. INTERVENTION(S): An experienced placental pathologist categorized placental pathology as anatomic, inflammatory, or vascular. Patient characteristics were compared by chi-squared tests, Student's t-test, or nonparametric tests. Multivariate logistic regression models were used to compare placental pathology between pregnancies conceived with and without ART. MAIN OUTCOME MEASURE(S): Incidence of anatomic, inflammatory, and vascular placental pathology. RESULT(S): There was a higher incidence of placental pathology in the ART group (n = 511) than in the non-ART group (n = 121), specifically anatomic (adjusted odds ratio [aOR] 2.50, 95% confidence interval [CI] 1.42-4.40) and vascular (aOR 2.00, 95% CI 1.13-3.53) pathology. These findings were driven primarily by the significantly higher odds of anatomic (aOR 2.97, 95% CI 1.55-5.66) and vascular (aOR 1.98, 95% CI 1.04-3.75) pathology observed in ICSI pregnancies. Single blastocyst transfers remained associated with increased anatomic pathology (ART: aOR 4.89, 95% CI 2.28-10.49; ICSI: aOR 3.38, 95% CI 1.49-7.71). CONCLUSION(S): Fresh embryo transfer is associated with increased anatomic and vascular placental pathology in term singleton live births compared with conception without ART. This finding should be investigated prospectively in a larger cohort of patients.

Development of the HIV360 international core set of outcome measures for adults living with HIV: A consensus process.

OBJECTIVES: HIV outcomes centre primarily around clinical markers with limited focus on patient-reported outcomes. With a global trend towards capturing the outcomes that matter most to patients, there is agreement that standardizing the definition of value in HIV care is key to their incorporation. This study aims to address the lack of routine, standardized data in HIV care. METHODS: An international working group (WG) of 37 experts and patients, and a steering group (SG) of 18 experts were convened from 14 countries. The project team (PT) identified outcomes by conducting a literature review, screening 1979 articles and reviewing the full texts of 547 of these articles. Semi-structured interviews and advisory groups were performed with the WG, SG and people living with HIV to add to the list of potentially relevant outcomes. The WG voted via a modified Delphi process - informed by six Zoom calls - to establish a core set of outcomes for use in clinical practice. RESULTS: From 156 identified outcomes, consensus was reached to include three patient-reported outcomes, four clinician-reported measures and one administratively reported outcome; standardized measures were included. The WG also reached agreement to measure 22 risk-adjustment variables. This outcome set can be applied to any person living with HIV aged > 18 years. CONCLUSIONS: Adoption of the HIV360 outcome set will enable healthcare providers to record, compare and integrate standardized metrics across treatment sites to drive quality improvement in HIV care.

Alcohol Consumption during COVID among Women with an Existing Alcohol-Use Disorder.

Prior to the pandemic, our research team implemented a randomized controlled trial of an intervention to reduce risk for alcohol-exposed pregnancy (AEP) in American Indian women. When active recruitment for the in-person trial was paused due to COVID, the research team moved to conducting follow-up surveys with participants who had completed the intervention to better understand changes to their alcohol use during the pandemic. We collected surveys from 62 American Indian women who had completed the Native CHOICES intervention. Baseline data collected pre-COVID included demographics and scores on the Alcohol Use Disorders Identification Test (AUDIT). Follow-up surveys conducted during the active pandemic period included a self-reported questionnaire about changes in drinking patterns. At pre-COVID baseline, all participants were engaged in heavy or binge drinking. At follow-up during COVID, 24.2% reported drinking more, and over half had at least one binge drinking episode. Approximately half reported reduced drinking. We found that risky drinking remained an issue during the pandemic for many American Indian women who had engaged in this behavior pre-COVID, while others reported reducing their alcohol consumption. As the pandemic abates, concerted efforts must be made to reach those with identified alcohol use disorders to offer resources and intervention as needed.

Vanishing Twins Conceived Through Fresh In Vitro Fertilization: Obstetric Outcomes and Placental Pathology.

OBJECTIVE: To characterize the obstetric outcomes and placental pathology in live births arising from vanishing twin pregnancies compared with nonreduced in vitro fertilization (IVF) pregnancies. METHODS: This is a retrospective cohort study of live births resulting from fresh embryo transfers after IVF cycles with autologous oocytes from 2004 through 2017 at a large academic fertility center. Clinical information and pathology reports were reviewed. Placental diagnoses were coded using established nosology by expert placental pathologists. Analysis of variance, Kruskal-Wallis, Pearson's χ, and Fisher exact tests were used, as appropriate, to compare pathology categories between pregnancy outcomes. Mixed effects logistic regression models were generated to reveal the association between pregnancy outcome and placenta pathology, controlling for pregnancies arising in the same woman and various suspected confounders. RESULTS: Of 905 fresh autologous IVF cycles with placental pathology available for review, we identified 73 vanishing twin pregnancies (8.1%), 556 singleton pregnancies (61.4%), and 276 twin pregnancies (30.5%). Vanishing twin syndrome was not associated with preterm delivery, route of delivery, growth restriction or other obstetric outcomes as compared with IVF singleton pregnancies. However, vanishing twin syndrome pregnancies showed distinctive placental pathologies including an increased rate of small placentas (less than the 10th percentile by weight), with more anatomical abnormalities than IVF singleton pregnancies (odds ratio 1.73, 95% CI 0.94-3.19; adjusted odds ratio 2.15, 95% CI 1.08-4.28). The frequency of placental vascular and inflammatory pathologies associated with IVF vanishing twin syndrome pregnancies were similar to that of IVF singleton pregnancies. Loss of a twin after 8 weeks of gestation was not associated with greater risks of placental pathologies. CONCLUSION: In vitro fertilization pregnancies affected by vanishing twin syndrome did not have significant differences in obstetric or perinatal outcomes as compared with twin or singleton gestations. However, early twin loss was potentially associated with differences in placental development associated with a higher rate of small placentas and other anatomic pathologies.

Placental pathology in live births conceived with in vitro fertilization after fresh and frozen embryo transfer.

BACKGROUND: The availability and use of frozen embryos after ovarian hyperstimulation for assisted reproduction has increased with improvement in vitrification techniques and the rise of preimplantation genetic testing. However, there are conflicting data regarding whether obstetric outcomes differ between fresh and frozen embryo transfer cycles. OBJECTIVE: To compare placental pathology from live births arising from fresh and frozen embryo transfer cycles. MATERIALS AND METHODS: A cohort of 1140 live births with placental pathology arising from autologous in vitro fertilization cycles with fresh or frozen programmed transfer performed at MGH Fertility Center between 2004 and 2017 was retrospectively reviewed. An experienced placental pathologist categorized the reported placental pathology as anatomic, infectious, inflammatory, or vascular/thrombotic. Our primary outcomes were differences in these placental pathologies between the 2 groups. Patient demographic, cycle, and birth outcomes were compared with the use of χ2 tests, Student t test, or nonparametric tests, as appropriate. Multivariate logistic regression models were used to compare placental pathology between the fresh and frozen transfer groups. RESULTS: Of the 1140 cycles included in our analysis, 929 arose from fresh embryo transfers (81.3%) and 211 arose from programmed frozen embryo transfers (18.5%). For both transfer types, the average age of the women at time of treatment was 35 years; mean body mass indices were within the normal range (23.6 kg/m2 for fresh transfers and 23.2 kg/m2 for frozen transfers, P = .26), and mean day 3 follicle-stimulating hormone values were 7.1 and 7.0 IU/L (P = .44), respectively. Deliveries occurred on average at 37.5 and 38.0 weeks' gestational age (P = .04) in the fresh versus frozen transfer group, with similar rates of obstetric complications. However, frozen transfers were more likely to be associated with marginal cord insertion (adjusted odds ratio, 1.87; confidence interval, 1.21, 2.91; P = .01), accessory lobe formation (adjusted odds ratio, 2.96; confidence interval, 1.12, 7.79; P = 0.03), subchorionic thrombi (adjusted odds ratio, 3.72; confidence interval, 1.80, 7.71; P < .001), and fetal vascular malperfusion characteristics with cord anomalies (adjusted odds ratio, 2.34; confidence interval, 1.22, 4.46; P = .01). These trends persisted when we analyzed day 5 transfers alone, and single frozen embryo transfers remained associated with increased rates of subchorionic thrombi compared to single fresh embryo transfers. CONCLUSION: Pregnancies arising from frozen embryo transfers demonstrated more anatomic and vascular placental pathology than those from fresh transfers in our cohort of patients, despite similar maternal outcomes. More research is needed to explore how these differences in pathology may influence obstetric and perinatal outcomes.

Primary odynophonia: When pain is out of proportion to dysphonia.

OBJECTIVES/HYPOTHESIS: Odynophonia is generally regarded as a symptom of a voice disorder. However, a subset of patients with odynophonia have debilitating pain out of proportion to the relatively mild degree of dysphonia and are not responsive to voice therapy. The goals of this study were to 1) describe the symptomatology of this subset of patients and differentiate it from typical odynophonia, 2) propose alternate models to explain this phenomenon of primary odynophonia, and 3) present a new treatment paradigm based on the proposed models. STUDY DESIGN: Case series. METHODS: Inclusion criteria were complaint of persistent pain associated with voicing, normal vocal fold mobility, complete glottic closure, and limited or lack of response of pain to voice therapy. Presenting symptoms, voice evaluation, and treatment outcomes were reviewed. RESULTS: Eleven patients fit the inclusion criteria. The degree of pain did not follow the trajectory of vocal improvement with therapy. The pain was stagnant or worsened with voice exercises. The most dramatic improvement came about in one patient who received false vocal fold Botox injections, and another who received thyrohyoid lidocaine/triamcinolone injection. We propose that these patients had developed primary odynophonia, in which the pain had become self-sustaining and no longer responded to correction of hyperfunctional vocal behavior. The mechanism of pain persistence may involve superior laryngeal neuralgia, cartilaginous or ligamentous inflammation, and/or central sensitization. CONCLUSIONS: A minority of patients have primary odynophonia distinct from typical odynophonia. Direct treatment of pain may be advisable prior to or in conjunction with voice therapy. LEVEL OF EVIDENCE: 4 Laryngoscope, 130:E183-E189, 2020.