Longitudinal observations of TFPI levels in paediatric Haemophilia A patients.

INTRODUCTION: Inhibition of tissue factor pathway inhibitor (TFPI) is a potential new mode of action to achieve haemostasis in haemophilia A and B patients. AIM: Knowledge about potential developmental changes of TFPI levels during childhood are a prerequisite to translate adult doses of TFPI inhibitors to doses in paediatric patients. METHODS: In this study we present longitudinal data for total TFPI concentrations (TFPI-T) and TFPI activity (TFPI-A) from 48 paediatric Haemophilia A patients in the age range from 3 to 18 years (2-12 observations per patient). RESULTS: TFPI-T and TFPI-A tend to decrease over age during childhood. Lowest values were observed between 12 and <18 years. On average, TFPI-T and TFPI-A were lower in adolescent haemophilia patients than in adult haemophilia patients. CONCLUSION: In summary, the presented information on TFPI levels in children adds to the current knowledge of developmental haemostasis and it can be helpful in evaluating how children respond to haemophilia treatment including the new class of anti-TFPI compounds.

COVID-19 vaccine effectiveness against SARS-CoV-2 infection during the Delta period, a nationwide study adjusting for chance of exposure, the Netherlands, July to December 2021.

BackgroundDifferential SARS-CoV-2 exposure between vaccinated and unvaccinated individuals may confound vaccine effectiveness (VE) estimates.AimWe conducted a test-negative case-control study to determine VE against SARS-CoV-2 infection and the presence of confounding by SARS-CoV-2 exposure.MethodsWe included adults tested for SARS-CoV-2 at community facilities between 4 July and 8 December 2021 (circulation period of the Delta variant). The VE against SARS-CoV-2 infection after primary vaccination with an mRNA (Comirnaty or Spikevax) or vector-based vaccine (Vaxzevria or Janssen) was calculated using logistic regression adjusting for age, sex and calendar week (Model 1). We additionally adjusted for comorbidity and education level (Model 2) and SARS-CoV-2 exposure (number of close contacts, visiting busy locations, household size, face mask wearing, contact with SARS-CoV-2 case; Model 3). We stratified by age, vaccine type and time since vaccination.ResultsVE against infection (Model 3) was 64% (95% CI: 50-73), only slightly lower than in Models 1 (68%; 95% CI: 58-76) and 2 (67%; 95% CI: 56-75). Estimates stratified by age group, vaccine and time since vaccination remained similar: mRNA VE (Model 3) among people ≥ 50 years decreased significantly (p = 0.01) from 81% (95% CI: 66-91) at < 120 days to 61% (95% CI: 22-80) at ≥ 120 days after vaccination. It decreased from 83% to 59% in Model 1 and from 81% to 56% in Model 2.ConclusionSARS-CoV-2 exposure did not majorly confound the estimated COVID-19 VE against infection, suggesting that VE can be estimated accurately using routinely collected data without exposure information.

Parental Enrollment Decision-Making for a Neonatal Clinical Trial.

OBJECTIVE: To describe the parental experience of recruitment and assess differences between parents who participated and those who declined to enroll in a neonatal clinical trial. STUDY DESIGN: This was a survey conducted at 12 US neonatal intensive care units of parents of infants who enrolled in the High-dose Erythropoietin for Asphyxia and encephaLopathy (HEAL) trial or who were eligible but declined enrollment. Questions assessed 6 factors of the parental experience of recruitment: (1) interactions with research staff; (2) the consent experience; (3) perceptions of the study; (4) decisional conflict; (5) reasons for/against participation; and (6) timing of making the enrollment decision. RESULTS: In total, 269 of 387 eligible parents, including 183 of 242 (75.6%) of those who enrolled their children in HEAL and 86 of 145 (59.3%) parents who declined to enroll their children in HEAL, were included in analysis. Parents who declined to enroll more preferred to be approached by clinical team members rather than by research team members (72.9% vs 49.2%, P = .005). Enrolled parents more frequently reported positive initial impressions (54.9% vs 10.5%, P < .001). Many parents in both groups made their decision early in the recruitment process. Considerations of reasons for/against participation differed by enrollment status. CONCLUSIONS: Understanding how parents experience recruitment, and how this differs by enrollment status, may help researchers improve recruitment processes for families and increase enrollment. The parental experience of recruitment varied by enrollment status. These findings can guide future work aiming to inform optimal recruitment strategies for neonatal clinical trials.

Recent development on the use of sublingual immunotherapy tablets for allergic rhinitis.

OBJECTIVE: Allergic rhinitis (AR) is an immunoglobulin (Ig) E-mediated inflammatory condition that causes sneezing, nasal congestion, rhinorrhea, and nasal itch. Although subcutaneous immunotherapy for the treatment of AR has been in use and well established as a treatment modality, sublingual immunotherapy (SLIT) is increasingly considered to be the safer and more convenient alternative. Thus, the objective of this review is to describe recent findings pertaining to the use of SLIT tablets (SLIT-T) for AR. DATA SOURCES: A database search (PubMed.gov) for articles published between January 1, 2017, and February 9, 2021, was conducted using the following key words: "allergic rhinitis," AND-ed "sublingual immunotherapy." Included were randomized placebo-controlled trials. Other experimental design studies were excluded. STUDY SELECTIONS: A total of 11 randomized placebo-controlled trials were selected for full-text review and included in the analysis. All studies investigated the use of SLIT on patients with seasonal AR (4 tree pollen, 1 grass pollen, and 1 Japanese cedar) or perennial AR (3 house dust mite). RESULTS: Our review of 7 recently published randomized placebo-controlled trials with 2348 subjects receiving SLIT reported increased efficacy, safety, supportive immunologic parameters (IgE and IgG4 pre- and posttreatment levels), and improved quality of life. All studies excluded subjects with overlapping seasonal or perennial allergens, a history of moderate-to-severe uncontrolled asthma, or reduced lung function. CONCLUSION: Our review highlights that SLIT is a safe and effective treatment that considerably reduces symptoms and medication requirements in AR and improves quality of life.

Outbreaks of mumps genotype G viruses in the Netherlands between October 2019 and March 2020: clusters associated with multiple introductions.

BACKGROUND: From October 2019-March 2020, several clusters of mumps cases were identified in the Netherlands. Our objective was to describe cluster-associated mumps virus transmission using epidemiological and molecular information in order to help future mumps outbreak investigation and control efforts. METHODS: An epidemiological cluster includes ≥ 2 mumps cases with at least an epidemiological-link to a laboratory-confirmed mumps case. A molecular group includes ≥ 2 mumps cases with identical mumps virus sequences. Cases with symptom onset date between 1 October 2019 and 31 March 2020 reported through the National Notifiable Diseases Surveillance System were included. We described epidemiological and clinical characteristics of mumps cases. Sequence data was obtained from selected regions of mumps virus genomes (2270 nucleotides). Associations between epidemiological and molecular information were investigated. RESULTS: In total, 102 mumps cases were notified (90% laboratory-confirmed, 10% epidemiologically-linked). 71 out of 102 cases were identified as part of an epidemiological cluster and/or molecular group. Twenty-one (30%) of 71 cases were identified solely from epidemiological information, 25 (35%) solely from molecular surveillance, and 25 (35%) using both. Fourteen epidemiological clusters were identified containing a total of 46 (range: 2-12, median: 3) cases. Complete sequence data was obtained from 50 mumps genotype G viruses. Twelve molecular groups were identified containing 43 (range: 2-13) cases, dispersed geographically and timewise. Combined information grouped seven epidemiological clusters into two distinct molecular groups. The first lasting for 14 weeks, the other for 6. Additionally, one molecular group was detected, linked by geography and time but without an epidemiological-link. CONCLUSIONS: Combined epidemiological and molecular information indicated ongoing mumps virus transmission from multiple introductions for extended time periods. Sequence analysis provided valuable insights into epidemiological clustering. If combined information is available in a timely manner, this would improve outbreak detection, generate further insight into mumps transmission, and guide necessary control measures.

Validating an Obstetrics and Gynaecology Longitudinal Integrated Clerkship Curriculum at the University of Toronto: A Four-Year Review.

The University of Toronto launched a longitudinal integrated clerkship (LIC) pilot project in 2014. Our aim was to evaluate LIC student outcomes in obstetrics and gynaecology compared with those of traditional block students. LIC and block students underwent identical evaluations, including written and oral exams, as well as clinical assessments from the ward. LIC student scores in each domain were compared with those of the traditional block students over 4 years. There were no differences in overall pass/fail status between LIC and block students. Thus, our LIC design could be appropriately modeled at other teaching institutions contemplating introducing an LIC stream.

Center, Gestational Age, and Race Impact End-of-Life Care Practices at Regional Neonatal Intensive Care Units.

OBJECTIVE: To assess the impact of intercenter variation and patient factors on end-of-life care practices for infants who die in regional neonatal intensive care units (NICUs). STUDY DESIGN: We conducted a retrospective cohort analysis using the Children's Hospital Neonatal Database during 2010-2016. A total of 6299 nonsurviving infants cared for in 32 participating regional NICUs were included to examine intercenter variation and the effects of gestational age, race, and cause of death on 3 end-of-life care practices: do not attempt resuscitation orders (DNR), cardiopulmonary resuscitation within 6 hours of death (CPR), and withdrawal of life-sustaining therapies (WLST). Factors associated with these practices were used to develop a multivariable equation. RESULTS: Dying infants in the cohort underwent DNR (55%), CPR (21%), and WLST (73%). Gestational age, cause of death, and race were significantly and differently associated with each practice: younger gestational age (<28 weeks) was associated with CPR (OR 1.7, 95% CI 1.5-2.1) but not with DNR or WLST, and central nervous system injury was associated with DNR (1.6, 1.3-1.9) and WLST (4.8, 3.7-6.2). Black race was associated with decreased odds of WLST (0.7, 0.6-0.8). Between centers, practices varied widely at different gestational ages, race, and causes of death. CONCLUSIONS: From the available data on end-of-life care practices for regional NICU patients, variability appears to be either individualized or without consistency.

Direct comparison of two extended half-life PEGylated recombinant FVIII products: a randomized, crossover pharmacokinetic study in patients with severe hemophilia A.

An open-label, crossover randomized study was performed to compare the pharmacokinetics (PK) of damoctocog alfa pegol and rurioctocog alfa pegol, two recombinant factor VIII (FVIII) products indicated in patients with hemophilia A, both conjugated to polyethylene glycol to reduce clearance and extend time in circulation. Adult patients (N = 18) with severe hemophilia A (FVIII < 1 IU/dL), previously treated with any FVIII product for ≥ 150 exposure days, were randomized to receive a single 50 IU/kg infusion of damoctocog alfa pegol followed by rurioctocog alfa pegol, or vice versa, with ≥ 7-day washout between doses. FVIII activity was measured using the one-stage clotting assay. PK parameters, including area under the curve from time 0 to the last data point (AUC0-tlast, primary parameter), dose-normalized AUC (AUCnorm), and time to threshold, were calculated based on 11 time points between 0.25 and 120 h post-dose and evaluated using a noncompartmental model. Due to differences in batch-specific vial content used for the study, actual administered median doses were 54.3 IU/kg for damoctocog alfa pegol and 61.4 IU/kg for rurioctocog alfa pegol. Based on actual dosing, a significantly higher geometric mean (coefficient of variation [%CV]) AUCnorm was observed for damoctocog alfa pegol (43.8 h kg/dL [44.0]) versus rurioctocog alfa pegol (36.0 h kg/dL [40.1, P < 0.001]). Based on population PK modeling, median time to reach 1 IU/dL was 16 h longer for damoctocog alfa pegol compared with rurioctocog alfa pegol. No adverse events or any immunogenicity signals were observed. Overall, damoctocog alfa pegol had a superior PK profile versus rurioctocog alfa pegol. Trial registration number: NCT04015492 ( ClinicalTrials.gov identifier). Date of registration: July 9, 2019.

Ebola Virus Infection Associated with Transmission from Survivors.

Ebola virus (EBOV) can persist in immunologically protected body sites in survivors of Ebola virus disease, creating the potential to initiate new chains of transmission. From the outbreak in West Africa during 2014-2016, we identified 13 possible events of viral persistence-derived transmission of EBOV (VPDTe) and applied predefined criteria to classify transmission events based on the strength of evidence for VPDTe and source and route of transmission. For 8 events, a recipient case was identified; possible source cases were identified for 5 of these 8. For 5 events, a recipient case or chain of transmission could not be confidently determined. Five events met our criteria for sexual transmission (male-to-female). One VPDTe event led to at least 4 generations of cases; transmission was limited after the other events. VPDTe has increased the importance of Ebola survivor services and sustained surveillance and response capacity in regions with previously widespread transmission.

Direct comparison of two extended-half-life recombinant FVIII products: a randomized, crossover pharmacokinetic study in patients with severe hemophilia A.

BAY 94-9027 is an extended-half-life, recombinant factor VIII (rFVIII) product conjugated with a 60-kDa branched polyethylene glycol (PEG) molecule indicated for use in previously treated patients (aged ≥ 12 years) with hemophilia A. This randomized, open-label, two-way crossover study compared the pharmacokinetics (PK) of BAY 94-9027 and rFVIII Fc fusion protein (rFVIIIFc) in patients with hemophilia A. Patients aged 18-65 years with FVIII < 1% and ≥ 150 exposure days to FVIII were randomized to receive intravenous single-dose BAY 94-9027 60 IU/kg followed by rFVIIIFc 60 IU/kg or vice versa, with ≥ 7-day wash-out between doses. FVIII activity was measured by one-stage assay. PK parameters, including area under the curve from time 0 to the last data point (AUClast, primary parameter), half-life, and clearance were calculated. Eighteen patients were randomized and treated. No adverse events were observed. In the analysis set excluding one outlier, geometric mean (coefficient of variation [%CV, 95% confidence interval {CI}]) AUClast was significantly higher for BAY 94-9027 versus rFVIIIFc (2940 [37.8, 2440-3550] IU h/dL versus 2360 [31.8, 2010-2770] IU h/dL, p = 0.0001). A population PK model was developed to simulate time to reach FVIII threshold levels; median time to 1 IU/dL was approximately 13 h longer for BAY 94-9027 versus rFVIIIFc after a single infusion of 60 IU/kg. In conclusion, BAY 94-9027 had a superior PK profile versus rFVIIIFc. ClinicalTrials.gov : NCT03364998.

The State of Needlestick Training for Undergraduate Medical Students at Canadian Universities.

Canadian undergraduate medical students sustain needlestick injuries, which have adverse implications, including blood-borne illnesses and personal anxiety. This study sought to determine students' needle handling efficacy and to examine the prevalence of formal training around needlestick safety and reporting procedures both nationally and, specifically, within the University of Toronto in Toronto, Ontario (U of T). A seven-question survey electronic survey was distributed to 116 undergraduate medical education (UME) leaders practising in high-risk rotations at 13 Canadian universities. Additionally, an eight-question survey was delivered electronically to 428 residents, fellows, and faculty in the Department of Obstetrics and Gynaecology at the U of T. A total of 34% of UME leaders and 36% from the U of T responded. Of UME respondents, 53% reported that their institution lacks needlestick training, and 35% were unsure whether their institution provides reporting instruction. At the U of T, 53% were "concerned" or "very concerned" that students pose a risk to themselves, and 27% "disagreed" or "strongly disagreed" that students handle instruments correctly. Our findings suggest that needlestick safety training for medical students across Canadian universities is insufficient. It is concerning that students are frequently exposed to patients in high-risk and surgically intensive rotations, despite their inexperience with needles. Furthermore, non-reporting among students may prevent them from receiving early prophylaxis or treatment. There is a need for the national implementation of a standardized and formalized needlestick safety curriculum for medical students before and during clerkship.

Bridging the Gap: Incorporating Simulation into Obstetrics and Gynaecology Undergraduate Medical Education.

INTRODUCTION: Currently, simulation training is not part of the clinical clerkship rotation in obstetrics and gynaecology (OB/GYN) at the University of Toronto. Instead, students are taught formally through lectures and informally on the ward or in the operating room. This study aimed to incorporate simulation using a high fidelity postpartum hemorrhage (PPH) workshop into the teaching curriculum, with the goal of improving both medical knowledge of PPH and nontechnical skills (NTS). METHOD: A novel teaching session was introduced for the third-year clerks on their OB/GYN rotation. Students (n = 88) were invited to participate in the research component to evaluate the effectiveness of this session. Students' (n = 83) baseline knowledge of PPH and teamwork attitudes were measured using a multiple-choice questionnaire (MCQ) and the TeamSTEPPS Questionnaire. Students participated in small-group learning about PPH and NTS, followed by a high-fidelity PPH simulation using a Laerdal SimMom Mannequin in a mock operating room. Students were debriefed, followed by a different MCQ and the TeamSTEPPS Questionnaire. RESULTS: Statistically significant improvements in students' comprehension (MCQ scores 63.9% vs. 76.5%, P < 0.05) and NTS (4.35/5 vs. 4.51/5, P < 0.05) were noted after simulation. The majority (92%) of students agreed that this method of learning was more enjoyable than traditional methods. CONCLUSIONS: Simulation in undergraduate education offers an exciting alternative to deliver information that is traditionally taught with didactic sessions while incorporating essential NTS. The authors hope that this study will encourage discussion of current simulation practices across Canada and standardized simulation techniques in OB/GYN.

A Novel Approach to Simulation-Based Perineal Repair in Undergraduate Medical Education.

INTRODUCTION: There is no formalized hands-on teaching of suturing skills for clerkship students during their dedicated obstetrics and gynaecology (OB/GYN) teaching sessions at the University of Toronto. Nevertheless, the students are exposed to suturing during gynaecologic surgery, Caesarean sections, and perineal repairs. As a result, a formal pilot workshop on knot-tying and perineal laceration repair was developed for incorporation into the third-year clerkship curriculum with the goals of increasing students' knowledge and technical skills. METHODS: Participants consisted of students enrolled in their OB/GYN clerkship rotation at St. Michael's Hospital at the University of Toronto from December 2016 to August 2017. Prior to the workshop, students' (n = 82) baseline knowledge of perineal lacerations was assessed with a pre-test quiz and their knot-tying speeds (two hand-ties and two instrument ties) were recorded. Students were then taught perineal anatomy, laceration types and repair techniques, suturing, and knot-tying. Under direct supervision, students practiced the technical skills for 45 minutes. Knowledge and knot-tying speeds were then reassessed following the educational session. RESULTS: There was a statistically significant improvement in both knowledge (51% to 71%; P < 0.05) and technical skills (258.8 seconds to 197.4 seconds; P < 0.05) after the workshop. Importantly, 94% of students "agreed" or "strongly agreed" that this method of learning was more enjoyable than traditional methods. CONCLUSIONS: This pilot project demonstrates that a formal hands-on workshop improves medical knowledge, technical skills, and student satisfaction. This has the potential for students to have increased opportunities at the bedside, with higher patient acceptance and safety.

A Validated Method for Identifying Unplanned Pediatric Readmission.

OBJECTIVE: To validate the accuracy of pre-encounter hospital designation as a novel way to identify unplanned pediatric readmissions and describe the most common diagnoses for unplanned readmissions among children. STUDY DESIGN: We examined all hospital discharges from 2 tertiary care children's hospitals excluding deaths, normal newborn discharges, transfers to other institutions, and discharges to hospice. We performed blinded medical record review on 641 randomly selected readmissions to validate the pre-encounter planned/unplanned hospital designation. We identified the most common discharge diagnoses associated with subsequent 30-day unplanned readmissions. RESULTS: Among 166,994 discharges (hospital A: n = 55,383; hospital B: n = 111,611), the 30-day unplanned readmission rate was 10.3% (hospital A) and 8.7% (hospital B). The hospital designation of "unplanned" was correct in 98% (hospital A) and 96% (hospital B) of readmissions; the designation of "planned" was correct in 86% (hospital A) and 85% (hospital B) of readmissions. The most common discharge diagnoses for which unplanned 30-day readmissions occurred were oncologic conditions (up to 38%) and nonhypertensive congestive heart failure (about 25%), across both institutions. CONCLUSIONS: Unplanned readmission rates for pediatrics, using a validated, accurate, pre-encounter designation of "unplanned," are higher than previously estimated. For some pediatric conditions, unplanned readmission rates are as high as readmission rates reported for adult conditions. Anticipating unplanned readmissions for high-frequency diagnostic groups may help focus efforts to reduce the burden of readmission for families and facilities. Using timing of hospital registration in administrative records is an accurate, widely available, real-time way to distinguish unplanned vs planned pediatric readmissions.

Spectrum of ocular diseases in patients attending eye camps in Andaman and Nicobar.

BACKGROUND: Andaman and Nicobar Island is a group of 572 islands with a population of 3,80,500. The only service hospital as well as govt hospital is situated at its capital, Portblair. The islands are interconnected only by sea passage and to reach the capital by this route it sometimes takes two days. METHODS: The objective of this study is to assess the spectrum of different ocular diseases in remote islands of Andaman and Nicobar. Author had conducted various camps on these remote islands as a community outreach programme over two years. RESULTS: Top eye diseases found were refractive error (35%), cataract (22%), conjunctival infammatory disease (15%), glaucoma cases (07%), pterygium (07%), NLDO (02%) and uveitis (02%). Out of total 132 cataract patients screened, 32 patients (approximately 24%) were operated in INHS Dhanvantari at free of cost with help of NPCB (National Programme for Control of Blindness). CONCLUSION: This was the first kind of study conducted on these remote islands to know the prevalence of different ocular diseases. The important point to be seen in this study was unawareness of glaucoma and cataract load. No optometrist was posted in the PHCs to provide primary eye care like prescribing glasses, which is also a big concern.

Development and validation of the PROcedural Sedation Assessment Survey (PROSAS) for assessment of procedural sedation quality.

BACKGROUND: More than 20 million invasive procedures are performed annually in the United States. The vast majority are performed with moderate sedation or deep sedation, yet there is limited understanding of the drivers of sedation quality and patient satisfaction. Currently, the major gap in quality assurance for invasive procedures is the lack of procedural sedation quality measures. OBJECTIVE: To develop and validate a robust, patient-centered measure of procedural sedation quality, the PROcedural Sedation Assessment Survey (PROSAS). DESIGN: Through a series of interviews with patients, proceduralists, nurses, anesthesiologists, and an interactive patient focus group, major domains influencing procedural sedation quality were used to create a multipart survey. The pilot survey was administered and revised in sequential cohorts of adults receiving moderate sedation for GI endoscopy. After revision, the PROSAS was administered to a validation cohort. SETTING: GI endoscopy unit. PATIENTS: A expert panel of proceduralists, nurses, and anesthesiologists, an initial survey development cohort of 40 patients, and a validation cohort of 858 patients undergoing sedation for outpatient GI endoscopy with additional surveys completed by the gastroenterologist, procedure nurse, and recovery nurse. MAIN OUTCOMES AND MEASUREMENTS: Survey characteristics of the PROSAS. RESULTS: Patients were able to independently complete the PROSAS after procedural sedation before discharge. Of the patients, 91.6% reported minimal discomfort; however, 8.4% of patients reported significant discomfort and 2.4% of patients experienced hemodynamic and/or respiratory instability. There was a high correlation between patient-reported intraprocedure discomfort and both clinician assessments of procedural discomfort and patient recall of procedural pain 24 to 48 hours post procedure (P < .001 for all), suggesting high external validity. LIMITATIONS: Single-center study, variability of sedation technique between providers, inclusion of patients with chronic pain taking analgesics. CONCLUSIONS: The PROSAS is a clinically relevant, patient-centered, easily administered instrument that allows for standardized evaluation of procedural sedation quality. The PROSAS may be useful in both research and clinical settings.