In Utero Enzyme-Replacement Therapy for Infantile-Onset Pompe's Disease.

Patients with early-onset lysosomal storage diseases are ideal candidates for prenatal therapy because organ damage starts in utero. We report the safety and efficacy results of in utero enzyme-replacement therapy (ERT) in a fetus with CRIM (cross-reactive immunologic material)-negative infantile-onset Pompe's disease. The family history was positive for infantile-onset Pompe's disease with cardiomyopathy in two previously affected deceased siblings. After receiving in utero ERT and standard postnatal therapy, the current patient had normal cardiac and age-appropriate motor function postnatally, was meeting developmental milestones, had normal biomarker levels, and was feeding and growing well at 13 months of age.

Apolipoprotein A1 and high-density lipoprotein limit low-density lipoprotein transcytosis by binding SR-B1.

Atherosclerosis results from the deposition and oxidation of LDL and immune cell infiltration in the sub-arterial space leading to arterial occlusion. Studies have shown that transcytosis transports circulating LDL across endothelial cells lining blood vessels. LDL transcytosis is initiated by binding to either scavenger receptor B1 (SR-B1) or activin A receptor-like kinase 1 on the apical side of endothelial cells leading to its transit and release on the basolateral side. HDL is thought to partly protect individuals from atherosclerosis due to its ability to remove excess cholesterol and act as an antioxidant. Apolipoprotein A1 (APOA1), an HDL constituent, can bind to SR-B1, raising the possibility that APOA1/HDL can compete with LDL for SR-B1 binding, thereby limiting LDL deposition in the sub-arterial space. To examine this possibility, we used in vitro approaches to quantify the internalization and transcytosis of fluorescent LDL in coronary endothelial cells. Using microscale thermophoresis and affinity capture, we find that SR-B1 and APOA1 interact and that binding is enhanced when using the cardioprotective variant of APOA1 termed Milano (APOA1-Milano). In male mice, transiently increasing the levels of HDL reduced the acute deposition of fluorescently labeled LDL in the atheroprone inner curvature of the aorta. Reduced LDL deposition was also observed when increasing circulating wild-type APOA1 or the APOA1-Milano variant, with a more robust inhibition from the APOA1-Milano. The results suggest that HDL may limit SR-B1-mediated LDL transcytosis and deposition, adding to the mechanisms by which it can act as an atheroprotective particle.

Guideline No. 448: Prevention of Rh D Alloimmunization.

OBJECTIVE: This guideline provides recommendations for the prevention of Rh D alloimmunization (isoimmunization) in pregnancy, including parental testing, routine postpartum and antepartum prophylaxis, and other clinical indications for prophylaxis. Prevention of red cell alloimmunization in pregnancy with atypical antigens (other than the D antigen), for which immunoprophylaxis is not currently available, is not addressed in this guideline. TARGET POPULATION: All Rh D-negative pregnant individuals at risk for Rh D alloimmunization due to potential exposure to a paternally derived fetal Rh D antigen. OUTCOMES: Routine postpartum and antepartum Rh D immunoprophylaxis reduces the risk of Rh D alloimmunization at 6 months postpartum and in a subsequent pregnancy. BENEFITS, HARMS, AND COSTS: This guideline details the population of pregnant individuals who may benefit from Rho(D) immune globulin (RhIG) immunoprophylaxis. Thus, those for whom the intervention is not required may avoid adverse effects, while those who are at risk of alloimmunization may mitigate this risk for themselves and/or their fetus. EVIDENCE: For recommendations regarding use of RhIG, Medline and Medline in Process via Ovid and Embase Classic + Embase via Ovid were searched using both the trials and observational studies search strategies with study design filters. For trials, the Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Database of Abstracts of Reviews of Effects via Ovid were also searched. All databases were searched from January 2000 to November 26, 2019. Studies published before 2000 were captured from the grey literature of national obstetrics and gynaecology specialty societies, luminary specialty journals, and bibliographic searching. A formal process for the systematic review was undertaken for this update, as described in the systematic review manuscript published separately. VALIDATION METHODS: The authors rated the quality of evidence and strength of recommendations using the SOGC's modified GRADE approach. See Appendix A (Tables A1 for definitions and A2 for interpretations of strong and conditional [weak] recommendations). INTENDED AUDIENCE: The intended users of this guideline include prenatal care providers such as obstetricians, midwives, family physicians, emergency room physicians, and residents, as well as registered nurses and nurse practitioners. TWEETABLE ABSTRACT: An updated Canadian guideline for prevention of Rh D alloimmunization addresses D variants, cffDNA for fetal Rh type, and updates recommendations on timing of RhIG administration. SUMMARY STATEMENTS: RECOMMENDATIONS.

Canadian Association of Radiologists Obstetrics and Gynecology Diagnostic Imaging Referral Guideline.

The Canadian Association of Radiologists (CAR) Obstetrics and Gynecology Expert Panel consists of radiologists specializing in obstetrics and gynecology, obstetrics and gynecology physicians, a patient advisor, and an epidemiologist/guideline methodologist. After developing a list of 12 clinical/diagnostic scenarios, a systematic rapid scoping review was undertaken to identify systematically produced referral guidelines that provide recommendations for one or more of these clinical/diagnostic scenarios. Recommendations from 46 guidelines and contextualization criteria in the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) for guidelines framework were used to develop 68 recommendation statements across the 12 scenarios related to the evaluation of obstetrics and gynecology clinical and diagnostic scenarios. This guideline presents the methods of development and the imaging recommendations for a variety of obstetrical and gynecological conditions including pregnancy assessment, recurrent first trimester pregnancy loss, post-partum indications, disorders of menstruation, localization of intra-uterine contraceptive device, infertility assessment, assessment of adnexal mass, pelvic pain of presumed gynecological origin, and pelvic floor evaluation.

Transcellular vesicular transport in epithelial and endothelial cells: Challenges and opportunities.

Vesicle-mediated transcellular transport or simply "transcytosis" is a cellular process used to shuttle macromolecules such as lipoproteins, antibodies, and albumin from one surface of a polarized cell to the other. This mechanism is in contrast to the transit of small molecules such as anions, cations and amino acids that occur via uptake, diffusion through the cytosol and release and is also distinct from paracellular leak between cells. Importantly, transcytosis has evolved as a process to selectively move macromolecules between 2 neighboring yet unique microenvironments within a multicellular organism. Examples include the movement of lipoproteins out of the circulatory system and into tissues and the delivery of immunoglobulins to mucosal surfaces. Regardless of whether the transport is conducted by endothelial or epithelial cells, the process often involves receptor-mediated uptake of a ligand into an endocytic vesicle, regulated transit of the carrier through the cytoplasm and release of the cargo via an exocytic event. While transcytosis has been examined in detail in epithelial cells, for both historical and technical reasons, the process is less understood in endothelial cells. Here, we spotlight aspects of epithelial transcytosis including recent findings and review the comparative dearth of knowledge regarding the process in endothelial cells highlighting the opportunity for further study.

Development of a toolkit for educators of the wheelchair service provision process: the Seating and Mobility Academic Resource Toolkit (SMART).

BACKGROUND: Insufficient wheelchair training among rehabilitation professionals has been identified as an important factor that hinders access to appropriate wheelchair services. The aim of this study was to develop a toolkit to promote the integration of wheelchair education into academic curricula of rehabilitation programs. METHODS: A participatory action research design was carried out in three phases: (1) development of the Initial and Alpha Versions involving secondary analyses of surveys (n = 72), interviews (n = 14), and academic training partners meeting presentations (n = 16); (2) development of the Beta Version based on feedback from collaborators (n = 21); and (3) development of the Launch Version based on feedback from participants attending presentations of the Beta Version at conferences, symposiums, and webinars (n = 94). RESULTS: Over 100 individuals participated in reviews of the Seating and Mobility Academic Resource Toolkit (SMART). Initial development addressed modifiable factors that perpetuate insufficient wheelchair education in academic curricula (e.g., limited awareness, limited expertise). Internal feedback on the web-based Alpha Version resulted in modifications of appearance and multimedia, structure and design, and navigation. External feedback then led primarily to fine-tuning the navigation of SMART. Positive reviews were received from global wheelchair professionals (i.e., educators, researchers, clinicians). The Launch Version of the SMART (smart.wheelchairnetwork.org) provides a forum for sharing and accessing resources to inform the integration and enhancement of wheelchair content into university rehabilitation programs. CONCLUSIONS: As an open-source open-access online "living document," SMART has the potential to promote the integration of wheelchair service provision education into academic curricula of rehabilitation programs. Future studies will explore the ease of use and the effectiveness of the SMART.

"A change in perspective": Exploring the experiences of adolescents with hereditary tumor predisposition.

BACKGROUND: Hereditary tumor predisposition syndromes (HTPSs) are being recognized more frequently in the etiology of pediatric cancer. Previous research indicates that disclosure of tumor susceptibility is a significant event in adolescents' lives. Insight into adolescents' adjustment to knowledge of their syndromes can guide healthcare delivery, particularly genetic counseling. This study explored the experiences of adolescents with hereditary tumor predisposition and their perceptions of living at risk. METHODS: Seven adolescents, ages 14 to 17, representing six different childhood-onset HTPSs, were purposively sampled and interviewed using a study-specific semistructured interview guide. We explored the disclosure process, support systems, and the perceived benefits and harms of knowledge of hereditary tumor susceptibility. Interview transcripts were analyzed via interpretive description. RESULTS: Three major themes emerged from the data: (1) The benefits of knowledge outweigh the harms; (2) context surrounding genetic testing must be recognized; and (3) self-concept is influenced but not defined by tumor risk. CONCLUSIONS: We conclude that adolescents recognize the challenges associated with awareness of tumor predisposition but may also identify positive aspects in their experiences, reflecting a changed life perspective. Results of this exploratory study suggest strategies that can guide pretest and posttest genetic counseling of adolescents for HTPSs, facilitating the adaptive incorporation of genetic information into an adolescent's self-concept.

Intrauterine Interventions for the Treatment of Twin Anemia-Polycythemia Sequence: A Systematic Review.

BACKGROUND: Twin anemia-polycythemia sequence (TAPS) is a complication of monochorionic, multiple gestation pregnancies in which blood shunting through placental anastomoses results in chronic anemia in one fetus and chronic polycythemia in another. The outcomes of different treatment modalities for TAPS are not well known. OBJECTIVE: To determine the outcomes of the intrauterine interventions used to treat TAPS. STUDY DESIGN: A systematic literature search of MEDLINE, EMBASE, and CENTRAL was performed in June 2016. Primary outcomes were mortality, morbidity, and adverse perinatal outcomes. Data were summarized in the form of weighted means, and statistical difference was determined. RESULTS: Twenty-one articles were identified for inclusion in this review and were composed of 105 cases of TAPS. In the cases presented in the literature, there was no statistically significant difference in mortality, morbidity, or emergent Caesarean section rates between expectant management, intrauterine transfusion (IUT), and laser ablation therapy. Laser ablation therapy and IUT were found to have a significantly lower rate of adverse perinatal outcomes when compared to expectantly managed cases. CONCLUSIONS: The literature looking into the treatment of TAPS is very limited, with no randomized controlled trials and only one includable comparative study. Based on the data in the case report and case study literature, there is no mortality difference between any of the treatment modalities. Expectant management may be associated with an increase in adverse perinatal outcomes when compared to laser therapy and IUT. More comparative studies are needed to assist clinicians in adopting an evidence-based approach to the treatment of TAPS.

No. 133-Prevention of Rh Alloimmunization.

OBJECTIVE: To provide guidelines on use of anti-D prophylaxis to optimize prevention of rhesus (Rh) alloimmunization in Canadian women. OUTCOMES: Decreased incidence of Rh alloimmunization and minimized practice variation with regards to immunoprophylaxis strategies. EVIDENCE: The Cochrane Library and MEDLINE were searched for English-language articles from 1968 to 200 I, relating to the prevention of Rh alloimmunization. Search terms included: Rho(D) immune globulin, Rh iso- or aile-immunization, anti-D, anti-Rh, WinRho, Rhogam, and pregnancy. Additional publications were identified from the bibliographies of these articles. All study types were reviewed. Randomized controlled trials were considered evidence of highest quality, followed by cohort studies. Key individual studies on which the principal recommendations are based are referenced. Supporting data for each recommendation is briefly summarized with evaluative comments and referenced. VALUES: The evidence collected was reviewed by the Maternal-Fetal Medicine and Genetics Committees of The Society of Obstetricians and Gynaecologists of Canada (SOGC) and quantified using the Evaluation of Evidence guidelines developed by the Canadian Task Force on the Periodic Health Exam. RECOMMENDATIONS: VALIDATION: These guidelines have been reviewed by the MaternalFetal Medicine Committee and the Genetics Committee, with input from the Rh Program of Nova Scotia. Final approval has been given by the Executive and Council of The Society of Obstetricians and Gynaecologists of Canada. SPONSORS: The Society of Obstetricians and Gynaecologists of Canada.

Oocyte donation pregnancies and the risk of preeclampsia or gestational hypertension: a systematic review and metaanalysis.

The purpose of this study was to determine whether pregnancies that were achieved via oocyte donation, compared with pregnancies achieved via other assisted reproductive technology methods or natural conception, demonstrate increased risk of preeclampsia or gestational hypertension. Comparative studies of pregnancies that were achieved with oocyte donation vs other methods of assisted reproductive technology or natural conception with preeclampsia or gestational hypertension were included as 1 of the measured outcomes. Abstracts and unpublished studies were excluded. Two reviewers independently selected studies, which were assessed for quality with the use of methodological index for non-randomized studies, and extracted the data. Statistical analysis was conducted. Of the 523 studies that were reviewed initially, 19 comparative studies met the predefined inclusion and exclusion criteria and were included in the metaanalysis, which allowed for analysis of a total of 86,515 pregnancies. Our pooled data demonstrated that the risk of preeclampsia is higher in oocyte-donation pregnancies compared with other methods of assisted reproductive technology (odds ratio, 2.54; 95% confidence interval, 1.98-3.24; P < .0001) or natural conception (odds ratio, 4.34; 95% confidence interval, 3.10-6.06; P < .0001). The risk of gestational hypertension was also increased significantly in oocyte donation pregnancies in comparison with other methods of assisted reproductive technology (odds ratio, 3.00; 95% confidence interval, 2.44-3.70; P < .0001) or natural conception (odds ratio, 7.94; 95% confidence interval, 1.73-36.36; P = .008). Subgroup analysis that was conducted for singleton and multiple gestations demonstrated a similar risk for preeclampsia and gestational hypertension in both singleton and multiple gestations. This metaanalysis provides further evidence that supports that egg donation increases the risk of preeclampsia and gestational hypertension compared with other assisted reproductive technology methods or natural conception.

OUTPATIENT MEDICATION USE AND IMPLICATIONS FOR DENTAL CARE: GUIDANCE FOR CONTEMPORARY DENTAL PRACTICE.

BACKGROUND: Adverse effects of medication used in dental care are likely to increase as North Americans live longer, experience more and greater severity of chronic conditions and take more medications. Thus, documentation of medication use and the implications for contemporary dental practice is of increasing importance. METHODS: We recorded medication use in patients referred to a large private periodontal practice in Ottawa, Ontario. Patients self-reported medication use and medication allergies in their health history forms on admission. RESULTS: Of 322 sequential patients enrolled, 164 were female and the overall median age was 52 (range 6-94 years). Participants reported taking 249 unique medications in 28 categories. Two-thirds of patients (63.7%) were taking prescription or over-the-counter (OTC) medications or both. The average number of medications per patient was 1.9 (range 0-14). The average number of OTC medications per patient was 0.5 for those not taking prescription medications and 0.4 for patients taking prescription medications concurrently. The number of OTC products per patient was 0-7. CONCLUSIONS: Given the prevalence of the use of both prescription and OTC products, accurate recording of the medication profile is necessary in contemporary dental practice. Medication use and medication allergies provide information on patients' medical history and diagnoses that may have implications for their oral condition and delivery of dental care. Additional concerns include potential interactions between frequently used medications reported by patients and medications that are commonly used in dentistry. CLINICAL IMPLICATIONS: The increase in the use of multiple medications and OTC products by the outpatient community has an impact on dental care and prescribed medications in dental care. Thus, it is important to have a complete and accurate medication history to ensure a high standard of care in dental practice.

Mitotic regulation of SEPT9 protein by cyclin-dependent kinase 1 (Cdk1) and Pin1 protein is important for the completion of cytokinesis.

Precise cell division is essential for multicellular development, and defects in this process have been linked to cancer. Septins are a family of proteins that are required for mammalian cell division, but their function and mode of regulation during this process are poorly understood. Here, we demonstrate that cyclin-dependent kinase 1 (Cdk1) phosphorylates septin 9 (SEPT9) upon mitotic entry, and this phosphorylation controls association with the proline isomerase, Pin1. Both SEPT9 and Pin1 are critical for mediating the final separation of daughter cells. Expression of mutant SEPT9 that is defective in Pin1 binding was unable to rescue cytokinesis defects caused by SEPT9 depletion but rather induced dominant-negative defects in cytokinesis. However, unlike SEPT9 depletion, Pin1 was not required for the accumulation of the exocyst complex at the midbody. These results suggest that SEPT9 plays multiple roles in abscission, one of which is regulated by the action of Cdk1 and Pin1.

Delayed-Interval Delivery in Multiple Pregnancy: A Single-Center Experience of Five Cases.

Objectives To describe the obstetric management and perinatal outcomes in multiple pregnancies with delayed-interval delivery (DID) of the cotwin in a tertiary hospital. Methods This is a retrospective chart review of all cases of DID between December 2021 and 2022 at The Ottawa Hospital. Five cases of DID were identified and reviewed to obtain information on obstetric management and maternal-neonatal outcomes. We included eligible twins and triplets. No multiples were excluded. We obtained ethics approval for this case series. Results Four sets of dichorionic diamniotic twins and one trichorionic triamniotic triplet were included. Our patients were admitted between 17 3/7 and 21 5/7 weeks of gestation. We achieved an interval delivery range between 1 and 36 days. Four out of six multiples did not survive in DID. The two surviving newborns were born at 23 0/7 and 23 2/7 , stayed in the neonatal intensive care unit (NICU) for 111 and 131 days, discharged with a weight of 3,594 and 2,743 g, respectively. All DID cases were delivered spontaneously except for two patients that required augmentation due to maternal sepsis. Conclusion Despite the high risk of maternal, fetal, and neonatal morbidity and mortality, if delivery of the first twin occurs before 20 gestational weeks, DID could be considered in selected cases to improve outcomes for the cotwin.

Formulation development of a stable influenza recombinant neuraminidase vaccine candidate.

Current influenza vaccines could be augmented by including recombinant neuraminidase (rNA) protein antigen to broaden protective immunity and improve efficacy. Toward this goal, we investigated formulation conditions to optimize rNA physicochemical stability. When rNA in sodium phosphate saline buffer (NaPBS) was frozen and thawed (F/T), the tetrameric structure transitioned from a "closed" to an "open" conformation, negatively impacting functional activity. Hydrogen deuterium exchange experiments identified differences in anchorage binding sites at the base of the open tetramer, offering a structural mechanistic explanation for the change in conformation and decreased functional activity. Change to the open configuration was triggered by the combined stresses of acidic pH and F/T. The desired closed conformation was preserved in a potassium phosphate buffer (KP), minimizing pH drop upon freezing and including 10% sucrose to control F/T stress. Stability was further evaluated in thermal stress studies where changes in conformation were readily detected by ELISA and size exclusion chromatography (SEC). Both tests were suitable indicators of stability and antigenicity and considered potential critical quality attributes (pCQAs). To understand longer-term stability, the pCQA profiles from thermally stressed rNA at 6 months were modeled to predict stability of at least 24-months at 5°C storage. In summary, a desired rNA closed tetramer was maintained by formulation selection and monitoring of pCQAs to produce a stable rNA vaccine candidate. The study highlights the importance of understanding and controlling vaccine protein structural and functional integrity.

Associations between self-reported odour annoyance and volatile organic compounds in 'Chemical Valley', Sarnia, Ontario.

Annoyance produced by air pollution has been suggested as a useful proxy for determining ambient air pollution exposure. However, most of the studies, to date, have focused on nitrogen dioxide and sulphur dioxide, with no work done on volatile organic compounds (VOC). This study is aimed at examining the associations between odour annoyance and VOC in 'Chemical Valley', Sarnia, Ontario, Canada. Annoyance scores were extracted from a community health survey (N = 774), and exposures to VOC were estimated from respondents' six-digit alphanumeric postal codes using land use regression models. Univariate analyses were used to explore the relationships between odour annoyance and modelled pollutants, whilst multivariate ordinal logistic regression was utilized to examine the determinants of odour annoyance. The results indicate that odour annoyance is significantly associated with modelled benzene, toluene, ethylbenzene, o-xylene and (m + p) xylene (BTEX) pollutants. The findings also show that the determinants of odour annoyance in the context of VOC include gender, number of relatives in the community, perception of air pollution, community satisfaction, medical checkups, ability to cope with daily life demands and general symptoms. When compared, the analysis indicates that Sarnia residents respond to considerably lower BTEX concentrations than the allowable 'safe' levels in the province of Ontario. In general, the results exhibit a dose-response gradient with annoyance score increasing with rising modelled pollutant concentrations. The observed relationships suggest that odour annoyance might be a function of true exposure and may serve as a proxy for air quality and ambient air pollution monitoring. However, questionnaire-based odour annoyance scores need to be longitudinally validated across different geographical scales and pollutants if they are to be adopted at the national level.

Prevalence and Risk Factors for Moral Distress in Pediatric Oncology Health Care Professionals.

PURPOSE: Moral distress (MoD) is prevalent among health care professionals (HCPs) in oncology and is associated with burnout. The objectives of this study were to quantify MoD among pediatric oncology healthcare professionals (HCPs) at a Canadian quaternary care hospital, identify root causes, and evaluate change over time. METHODS: Eligible pediatric oncology HCPs were identified, and consenting participants completed the Measure of Moral Distress-Healthcare Professionals (MMD-HP) and MoD Thermometer (MDT) at baseline, followed by biweekly MDTs over 12 weeks. RESULTS: A total of 139 HCPs participated. The mean MMD-HP score was 123 ± 57.0, range 9-288. Demographic risk factors identified for elevated MMD-HP scores were female sex (female 127.1 and male 83.6, P = .01) and nursing role (nurse 136.3 and most responsible physician 85.3, P = .02). Higher MMD-HP scores were found in HCPs who were currently considering resigning because of MoD compared with those who were not (169.9 v 115.4, P < .001). Situations involving administration of treatment to children with poor prognosis cancers that was perceived to be overly aggressive were ranked as the greatest environmental contributor to MoD. Baseline and mean MDT scores over time strongly correlated with MMD-HP scores (P < .0001 and P = .0003, respectively), with mean MDT scores showing no significant fluctuation over the 12-week period. CONCLUSION: MoD was common among pediatric oncology HCPs. Risk factors for elevated levels of MoD included both demographic and environmental factors. Implementation of systems to improve team communication and decision making, especially in the care of patients with poor prognosis cancers, may affect HCP MoD.