Maldistribution of pulmonary blood flow in patients after the Fontan operation is associated with worse exercise capacity

Background

Maldistribution of pulmonary artery blood flow (MPBF) is a potential complication in patients who have undergone single ventricle palliation culminating in the Fontan procedure. Cardiovascular magnetic resonance (CMR) is the best modality that can evaluate MPBF in this population. The purpose of this study is to identify the prevalence and associations of MPBF and to determine the impact of MPBF on exercise capacity after the Fontan operation.

Methods

This retrospective single-center study included all patients after Fontan operation who had maximal cardiopulmonary exercise test (CPET) and CMR with flow measurements of the branch pulmonary arteries. MPBF was defined as >?20% difference in branch pulmonary artery flow. Exercise capacity was measured as percent of predicted oxygen consumption at peak exercise (% predicted VO₂). Linear and logistic regression models were used to determine univariate and multivariable predictors of exercise capacity and correlates of MPBF, respectively.

Results

A total of 147 patients who had CMR between 1999 and 2017 were included (median age at CMR 21.8?years [interquartile range (IQR) 16.5–30.6]) and the median time between CMR and CPET was 2.8?months [IQR 0–13.8]. Fifty-three patients (36%) had MPBF (95% CI 29–45%). The mean % predicted VO₂ was 63?±?16%. Patients with MPBF had lower mean % predicted VO₂ compared to patients without MPBF (60?±?14% versus 65?±?16%, p?=?0.04). On multivariable analysis, a lower % predicted VO₂ was independently associated with longer time since Fontan, higher ventricular mass-to-volume ratio, and MPBF. On multivariable analysis, only compression of the branch pulmonary arteries by the ascending aorta or aortic root was associated with MPBF (OR 6.5, 95% CI 5.6–7.4, p?<?0.001).

Conclusion

In patients after the Fontan operation, MPBF is common and is independently associated with lower exercise capacity. MPBF was most likely to be caused by pulmonary artery compression by the aortic root or the ascending aorta. This study identifies MPBF as an important risk factor and as a potential target for therapeutic interventions in this fragile patient population.

     

Problem-based learning in occupational therapy curriculum – implications and challenges

Purpose: Problem-based learning (PBL) is an educational method that fosters self-directed study in small groups. The purpose of this study was to describe the Tel Aviv University’s occupational therapy (OT) program and the challenges implementing such program. In addition, the study compared the PBL grades obtained by students who are native Hebrew speakers with those students who are native Arabic speakers; and, assessed the correlation between the grades in the PBL course and the grades in the clinical fieldwork studies.

Method: 166-second year OT undergraduate students participated. All completed three PBL courses and seven weeks of clinical fieldwork studies. Data collection included students’ grades in PBL course (based on PBL evaluation forms) and in clinical fieldwork studies (based on preceptor’s evaluation and a written assignment).

Results: Pearson correlations revealed significant correlations between PBL grades and clinical fieldwork studies grades. T-test analysis between students who are native Hebrew speakers and those who are native Arabic speakers revealed significant differences in PBL grades.

Conclusions: Findings imply partial congruence between students’ grades in the PBL course and their achievements in the fieldwork studies. Findings might suggest that adjustments should be made in order to assist students from minorities (challenged by language requirements) in gaining higher grades in the PBL program.

• Implications for Rehabilitation

• Problem-Based Learning (PBL) is an educational method, which fosters independent, self-directed study in small groups.

• PBL studies have the potential to prepare students for their clinical experience during studies.

• The PBL program should be adjusted for students from minorities (challenged by language requirements and different cultural backgrounds) in order to assist them in gaining more benefits from the program.

     

Short-term effect of morphine on the thyroid gland in male rats

Experiments were designed to demonstrate that morphine may exert a direct short-term effect on the hormone release of the thyroid gland. Groups of male rats were injected with single doses of 1, 5 and 10 mg/kg morphine, or with 2 mg/kg naloxone and in addition with morphine 30 min after naloxone and/or with naloxone 30 min after morphine pre-treatment. The rats were killed by decapitation 15, 30 and 60 min after the injection and serum was collected and stored for subsequent TSH, T4 and T3 radioassays. All doses of morphine resulted in an increase of serum T4 and T3 concentrations 15 and 30 min after the injection, with a tendency to return to control levels by the 60 min samples. Serum TSH concentrations were to suppressed by administration of 5 and 10 mg/kg but not by 1 mg/kg morphine. Naloxone treatment did not increase the T4 and T3 concentrations; however, serum TSH was elevated in the 15 min sample. Naloxone pre-treatment inhibited the morphine induced release of T4 and T3 into the serum, but naloxone administration after morphine pre-treatment failed to prevent the increase of T4 and T3 secretion. These data suggest that morphine may exert a short-term stimulatory effect on the thyroid gland with a concomitant inhibitory action on the hypothalamo-pituitary TSH system.     

Efficient maternal to neonatal transfer of antibodies against SARS-CoV-2 and BNT162b2 mRNA COVID-19 vaccine

BACKGROUNDThe significant risks posed to mothers and fetuses by COVID-19 in pregnancy have sparked a worldwide debate surrounding the pros and cons of antenatal SARS-CoV-2 inoculation, as we lack sufficient evidence regarding vaccine effectiveness in pregnant women and their offspring. We aimed to provide substantial evidence for the effect of the BNT162b2 mRNA vaccine versus native infection on maternal humoral, as well as transplacentally acquired fetal immune response, potentially providing newborn protection.METHODSA multicenter study where parturients presenting for delivery were recruited at 8 medical centers across Israel and assigned to 3 study groups: vaccinated (n = 86); PCR-confirmed SARS-CoV-2 infected during pregnancy (n = 65), and unvaccinated noninfected controls (n = 62). Maternal and fetal blood samples were collected from parturients prior to delivery and from the umbilical cord following delivery, respectively. Sera IgG and IgM titers were measured using the Milliplex MAP SARS-CoV-2 Antigen Panel (for S1, S2, RBD, and N).RESULTSThe BNT162b2 mRNA vaccine elicits strong maternal humoral IgG response (anti-S and RBD) that crosses the placenta barrier and approaches maternal titers in the fetus within 15 days following the first dose. Maternal to neonatal anti-COVID-19 antibodies ratio did not differ when comparing sensitization (vaccine vs. infection). IgG transfer ratio at birth was significantly lower for third-trimester as compared with second trimester infection. Lastly, fetal IgM response was detected in 5 neonates, all in the infected group.CONCLUSIONAntenatal BNT162b2 mRNA vaccination induces a robust maternal humoral response that effectively transfers to the fetus, supporting the role of vaccination during pregnancy.FUNDINGIsrael Science Foundation and the Weizmann Institute Fondazione Henry Krenter.     

Targeting oncogenic interleukin‐7 receptor signalling with N‐acetylcysteine in T cell acute lymphoblastic leukaemia

Activating mutations of the interleukin‐7 receptor (IL7R) occur in approximately 10% of patients with T cell acute lymphoblastic leukaemia (T‐ALL). Most mutations generate a cysteine at the transmembrane domain leading to receptor homodimerization through disulfide bond formation and ligand‐independent activation of STAT5. We hypothesized that the reducing agent N‐acetylcysteine (NAC), a well‐tolerated drug used widely in clinical practice to treat acetaminophen overdose, would reduce disulfide bond formation, and inhibit mutant IL7R‐mediated oncogenic signalling. We found that treatment with NAC disrupted IL7R homodimerization in IL7R‐mutant DND‐41 cells as assessed by non‐reducing Western blot, as well as in a luciferase complementation assay. NAC led to STAT5 dephosphorylation and cell apoptosis at clinically achievable concentrations in DND‐41 cells, and Ba/F3 cells transformed by an IL7R‐mutant construct containing a cysteine insertion. The apoptotic effects of NAC could be rescued in part by a constitutively active allele of STAT5. Despite using doses lower than those tolerated in humans, NAC treatment significantly inhibited the progression of human DND‐41 cells engrafted in immunodeficient mice. Thus, targeting leukaemogenic IL7R homodimerization with NAC offers a potentially effective and feasible therapeutic strategy that warrants testing in patients with T‐ALL.