Safety of the BNT162b2 mRNA Covid-19 Vaccine in a Nationwide Setting.

BACKGROUND: Preapproval trials showed that messenger RNA (mRNA)-based vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) had a good safety profile, yet these trials were subject to size and patient-mix limitations. An evaluation of the safety of the BNT162b2 mRNA vaccine with respect to a broad range of potential adverse events is needed. METHODS: We used data from the largest health care organization in Israel to evaluate the safety of the BNT162b2 mRNA vaccine. For each potential adverse event, in a population of persons with no previous diagnosis of that event, we individually matched vaccinated persons to unvaccinated persons according to sociodemographic and clinical variables. Risk ratios and risk differences at 42 days after vaccination were derived with the use of the Kaplan-Meier estimator. To place these results in context, we performed a similar analysis involving SARS-CoV-2-infected persons matched to uninfected persons. The same adverse events were studied in the vaccination and SARS-CoV-2 infection analyses. RESULTS: In the vaccination analysis, the vaccinated and control groups each included a mean of 884,828 persons. Vaccination was most strongly associated with an elevated risk of myocarditis (risk ratio, 3.24; 95% confidence interval [CI], 1.55 to 12.44; risk difference, 2.7 events per 100,000 persons; 95% CI, 1.0 to 4.6), lymphadenopathy (risk ratio, 2.43; 95% CI, 2.05 to 2.78; risk difference, 78.4 events per 100,000 persons; 95% CI, 64.1 to 89.3), appendicitis (risk ratio, 1.40; 95% CI, 1.02 to 2.01; risk difference, 5.0 events per 100,000 persons; 95% CI, 0.3 to 9.9), and herpes zoster infection (risk ratio, 1.43; 95% CI, 1.20 to 1.73; risk difference, 15.8 events per 100,000 persons; 95% CI, 8.2 to 24.2). SARS-CoV-2 infection was associated with a substantially increased risk of myocarditis (risk ratio, 18.28; 95% CI, 3.95 to 25.12; risk difference, 11.0 events per 100,000 persons; 95% CI, 5.6 to 15.8) and of additional serious adverse events, including pericarditis, arrhythmia, deep-vein thrombosis, pulmonary embolism, myocardial infarction, intracranial hemorrhage, and thrombocytopenia. CONCLUSIONS: In this study in a nationwide mass vaccination setting, the BNT162b2 vaccine was not associated with an elevated risk of most of the adverse events examined. The vaccine was associated with an excess risk of myocarditis (1 to 5 events per 100,000 persons). The risk of this potentially serious adverse event and of many other serious adverse events was substantially increased after SARS-CoV-2 infection. (Funded by the Ivan and Francesca Berkowitz Family Living Laboratory Collaboration at Harvard Medical School and Clalit Research Institute.).

Long-term outcome of neonates with suspected Hirschsprung's disease, but normal rectal biopsy.

BACKGROUND AND OBJECTIVES: Hirschsprung's disease (HD) must always be considered in very early-onset constipation. Although HD has a well-described clinical course, little is known about those neonates in whom HD was excluded. We aimed to describe the long-term clinical outcomes of neonates with a clinical suspicion of HD that was excluded by rectal suction biopsy. METHODS: This is a single-center double-cohort comparative study. Neonates who underwent rectal mucosa biopsy for suspected HD were age and sex matched with healthy controls. A survey on clinical outcomes, stooling patterns, and other gastrointestinal (GI)-related conditions was sent to parents. Pathology slides were re-reported by an experienced histopathologist blinded to the clinical data. RESULTS: A total of 51 neonates were included [25 cases, 26 controls; 41% males, median time of follow-up 4.25 years (interquartile range 2.7-6.9)]. Nine (36%) of patients in the case group required prolonged laxative use for constipation during the first year of life compared with 0 (0%) controls (P<0.001). This difference was maintained at the end of follow-up, with 5 (20%) versus 0 (0%), respectively (P=0.02). Case neonates were significantly more likely to be hospitalized or to be diagnosed with a chronic GI-related condition than the controls (33 vs. 12%, P=0.01; and 19 vs. 8%, P=0.04, respectively). CONCLUSION: Neonatal constipation is associated with long-term GI-related disorders and should be considered clinically significant even when the diagnosis of HD is excluded. Neonates with early-onset abnormal stooling patterns should be monitored with adequate pediatrician or pediatric gastroenterologist follow-up.

Skeletal ligament healing using the recombinant human amelogenin protein.

Injuries to ligaments are common, painful and debilitating, causing joint instability and impaired protective proprioception sensation around the joint. Healing of torn ligaments usually fails to take place, and surgical replacement or reconstruction is required. Previously, we showed that in vivo application of the recombinant human amelogenin protein (rHAM(+)) resulted in enhanced healing of the tooth-supporting tissues. The aim of this study was to evaluate whether amelogenin might also enhance repair of skeletal ligaments. The rat knee medial collateral ligament (MCL) was chosen to prove the concept. Full thickness tear was created and various concentrations of rHAM(+), dissolved in propylene glycol alginate (PGA) carrier, were applied to the transected MCL. 12 weeks after transection, the mechanical properties, structure and composition of transected ligaments treated with 0.5 µg/µl rHAM(+) were similar to the normal un-transected ligaments, and were much stronger, stiffer and organized than control ligaments, treated with PGA only. Furthermore, the proprioceptive free nerve endings, in the 0.5 µg/µl rHAM(+) treated group, were parallel to the collagen fibres similar to their arrangement in normal ligament, while in the control ligaments the free nerve endings were entrapped in the scar tissue at different directions, not parallel to the axis of the force. Four days after transection, treatment with 0.5 µg/µl rHAM(+) increased the amount of cells expressing mesenchymal stem cell markers at the injured site. In conclusion application of rHAM(+) dose dependently induced mechanical, structural and sensory healing of torn skeletal ligament. Initially the process involved recruitment and proliferation of cells expressing mesenchymal stem cell markers.

Scalloping is a reliable endoscopic marker for celiac disease.

BACKGROUND: Scalloping of duodenal folds noted on esophagogastroduodenoscopy (EGD) has been associated with various illnesses including celiac disease (CD). The aim of the present study was to examine the frequency of scalloping in pediatric patients undergoing EGD and to assess its significance in the diagnosis of CD. We also evaluated the association of scalloping with the histopathology and celiac serology in the subgroup of celiac patients. PATIENTS AND METHODS: All children (0-18 years) who underwent EGD at Shaare Zedek Medical Center for any reason during a 2.5-year period were retrospectively included, yielding a consecutive cohort without selection bias. Relevant data were obtained from the patient files. RESULTS: During the study period, 623 children underwent EGD of whom 149 (24%) were eventually diagnosed with CD. In 74/623children (12%), scalloping was seen and had a sensitivity of 48% (95% CI 0.40-0.57), specificity of 99% (0.98-0.99) and positive predictive value of 97% (0.9-0.99) to diagnose CD. The prevalence of scalloping increased with advancing stage of the Marsh classification from 33% (7/21) in Marsh 1 to 63% (34/54) in Marsh 3c (P < 0.001). Scalloping was associated with a significantly higher median tissue transglutaminase level (153 [IQR 98-168] versus 49 [IQR 11-143]; P = 0.011). CONCLUSION: The results suggest that the diagnosis of CD is almost certain if isolated scalloping is observed during EGD done to rule out CD. Thus, attention to this finding may serve as an additional tool in the diagnosis of CD.

Mathematical weighting of the pediatric Crohn's disease activity index (PCDAI) and comparison with its other short versions.

BACKGROUND: The Pediatric Crohn's Disease Activity Index (PCDAI) has become the standard outcome measure in pediatric Crohn's disease (CD) clinical research. Other versions have been proposed but without systematic evaluation. The aim was to assess validity and responsiveness of the abbreviated PCDAI (abbrPCDAI), short PCDAI (shPCDAI), and modified PCDAI (modPCDAI) as measures of disease activity and to compare these with a mathematically weighted version developed here (wPCDAI). METHODS: The raw data from four prospectively collected datasets were used, totaling 437 children with CD (including two clinical trials). Discriminant validity utilized physician global assessment of disease activity (PGA), and construct validity the correlation with PGA and laboratory results. Feasibility and face validity were ascertained by a survey of 33 experts in pediatric CD. RESULTS: The wPCDAI had better performance than the PCDAI in construct validity and responsiveness and it discriminated better between the disease activity categories (area under the receiver operator characteristic [ROC] 0.97; 95% confidence interval [CI]: 0.95-0.99). In comparison to the original PCDAI, the noninvasive versions (abbrPCDAI and shPCDAI) had lower face, construct, and discriminant validity but were judged to be significantly more feasible. The modPCDAI performed well in the construct validation but was consistently inferior in all other parameters. Cutoffs that correspond to remission, response, and gradations of disease activity were determined for each index. CONCLUSIONS: The newly weighted wPCDAI performed better than the original PCDAI and is more feasible. The noninvasive versions (shPCDAI and abbrPCDAI) are inferior to the full PCDAI, but when needed in retrospective studies either may be equally used.