Individualized norms of optimal fetal growth: fetal growth potential

OBJECTIVE: To demonstrate that individualized optimal fetal growth norms, accounting for physiologic and pathologic determinants of fetal growth, better identify normal and abnormal outcomes of pregnancy than existing methods. METHODS: In a prospective cohort of 38,033 singleton pregnancies, we identified 9,818 women with a completely normal outcome of pregnancy and characterized the physiologic factors affecting birth weight using multivariable regression. We used those physiologic factors to individually predict optimal growth trajectory and its variation, growth potential, for each fetus in the entire cohort. By comparing actual birth weight with growth potential, population, ultrasound, and customized norms, we calculated for each fetus achieved percentiles, by each norm. We then compared proportions of pregnancies classified as normally grown, between 10th and 90th percentile, or aberrantly grown, outside this interval, by growth potential and traditional norms, in 14,229 complicated pregnancies, 1,518 pregnancies with diabetes or hypertensive disorders, and 1,347 pregnancies with neonatal complications. RESULTS: Nineteen physiologic factors, associated with maternal characteristics and early placental function, were identified. Growth potential norms correctly classified significantly more pregnancies than population, ultrasound, or customized norms in complicated pregnancies (26.4% compared with 18.3%, 18.7%, 22.8%, respectively, all P<.05), pregnancies with diabetes or hypertensive disorders (37.3% compared with 23.0%, 28.0%, 34.0%, respectively, all P<.05) and neonatal complications (33.3% compared with 19.7%, 24.9%, 29.8%, respectively, all P<.05). CONCLUSION: Growth potential norms based on the physiologic determinants of birth weight are a better discriminator of aberrations of fetal growth than traditional norms. LEVEL OF EVIDENCE: II.     

Inherited thrombophilias and pre-eclampsia in Brazilian women

OBJECTIVE: The aim of the present study was to compare the distribution of G1691A, G20210A and C677T mutations in pre-eclamptic Brazilian women and in matched control women with an uncomplicated normal pregnancy. STUDY DESIGN: these mutations were investigated by PCR-RFLP in 83 normal pregnancies (control group) and in 30 pre-eclamptic pregnant women (severe form). RESULTS: G1691A mutation was detected neither in the control group nor in pre-eclamsia women. G20210A mutation was detected in heterozygosis in 3 (3.61%) control subjects, but not in pre-eclampsia group. C677T mutation was detected in homozygosis in 6 (7.23%) control subjects and 2 (6.67%) pre-eclamptic women and in heterozygosis in 31 (37.3%) control subjects and 12 (40%) pre-eclamptic women. Differences in the mutation frequencies detected in the two groups were not statistically significant. CONCLUSION: No correlation was observed between pre-eclampsia and presence of G1691A, G20210A and C677T mutations in Brazilian women.     

Dual IGF1R/IR inhibitors in combination with GD2-CAR T-cells display a potent anti-tumor activity in diffuse midline glioma H3K27M-mutant

BackgroundDiffuse midline gliomas (DMG) H3K27M-mutant, including diffuse intrinsic pontine glioma (DIPG), are pediatric brain tumors associated with grim prognosis. Although GD2-CAR T-cells demonstrated significant anti-tumor activity against DMG H3K27M-mutant in vivo, a multimodal approach may be needed to more effectively treat patients. We investigated GD2 expression in DMG/DIPG and other pediatric high-grade gliomas (pHGG) and sought to identify chemical compounds that would enhance GD2-CAR T-cell anti-tumor efficacy.MethodsImmunohistochemistry in tumor tissue samples and immunofluorescence in primary patient-derived cell lines were performed to study GD2 expression. We developed a high-throughput cell-based assay to screen 42 kinase inhibitors in combination with GD2-CAR T-cells. Cell viability, western blots, flow-cytometry, real time PCR experiments, DIPG 3D culture models, and orthotopic xenograft model were applied to investigate the effect of selected compounds on DIPG cell death and CAR T-cell function.ResultsGD2 was heterogeneously, but widely, expressed in the tissue tested, while its expression was homogeneous and restricted to DMG/DIPG H3K27M-mutant cell lines. We identified dual IGF1R/IR antagonists, BMS-754807 and linsitinib, able to inhibit tumor cell viability at concentrations that do not affect CAR T-cells. Linsitinib, but not BMS-754807, decreases activation/exhaustion of GD2-CAR T-cells and increases their central memory profile. The enhanced anti-tumor activity of linsitinib/GD2-CAR T-cell combination was confirmed in DIPG models in vitro, ex vivo, and in vivo.ConclusionOur study supports the development of IGF1R/IR inhibitors to be used in combination with GD2-CAR T-cells for treating patients affected by DMG/DIPG and, potentially, by pHGG.     

COVID-19 and Guillain-Barré syndrome: A single-center prospective case series with a 1-year follow-up

Single reports of Guillain-Barré syndrome (GBS) have been reported worldwide during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. While case reports are likely to be biased toward uncommon clinical presentations, systematic assessment of prospective series can highlight the true clinical features and spectrum. In this prospective, observational study, we included all consecutive patients who developed GBS. In patients with SARS-CoV-2 infection as antecedent, the time-gap between the infection and GBS onset had to be ≤30 days. The referral was a neurological University Research Hospital, in the Italian Region more severely involved by the pandemic, and hospitalizing both COVID+ and non-COVID neurological diseases. Clinical, laboratory, cerebrospinal fluid, and electromyographic features of GBS diagnosed between March 2020 and March 2021 were compared to a retrospective series of GBS diagnosed between February 2019 and February 2020 (control population). Nasopharyngeal swab was still positive at GBS onset in 50% of patients. Mild-to-moderate COVID-related pneumonia, as assessed by X-ray (6 patients) or X-ray plus computerized tomography (2 patients) co-occurred in 6 of 10 patients. GBS diagnosed during the pandemic period, including 10 COVID-GBS and 10 non–COVID-GBS, had higher disability on admission (P = .032) compared to the GBS diagnosed between February 2019 and 2020, possibly related to later hospital referral in the pandemic context. Compared to non–COVID-GBS (n = 10) prospectively diagnosed in the same period (March 2020–2021), post–COVID-GBS (n = 10) had a higher disability score on admission (P = .028), lower sum Medical Research Council score (P = .022) and lymphopenia (P = .025), while there were no differences in GBS subtype/variant, severity of peripheral involvement, prognosis and response to treatment. Cerebrospinal fluid search for SARS-CoV-2 RNA and antiganglioside antibodies were negative in all COVID+ patients. Temporal clustering of cases, coinciding with the waves of the pandemic, and concomitant reduction of the incidence of COVID-negative GBSs may indicate a role for SARS-CoV-2 infection in the development of GBS, although the association may simply be related to a bystander effect of systemic inflammation; lack of prevalence of specific GBS subtypes in post–COVID-GBS also support this view. GBS features and prognosis are not substantially different compared to non–COVID-GBS.     

The Impact of Omega-3 Supplements on Non-Surgical Periodontal Therapy: A Systematic Review

Aim: This systematic review examined the additional effect of taking omega-3 supplements on periodontal therapy. Methods: The focused question was “What is the possible effect of omega-3 supplementation concomitant to non-surgical periodontal therapy on clinical periodontal parameters?” Databases Cochrane, Embase, Google Scholar, PubMed, and Web of Science (January-July 2021) were searched to identify appropriate studies. Randomized clinical trials (RCT) about non-surgical therapy with omega-3 supplementation, with at least 3 months of supplementation period were included. Cochrane risk of bias tool version 2 and Grading of Recommendations Assessment, Development, and Evaluation were used. Results: A total of 1556 studies were found, of which eight studies met the inclusion criteria. All eight studies evaluated periodontal probing depth and clinical attachment loss; plaque and gingival inflammation were evaluated in seven studies. High variety of omega-3 dosage, different study lengths, questionable results from periodontal therapy (including test and control groups), high risk of bias and moderate quality of evidence prevented a satisfactory conclusion regarding the benefits of omega-3 supplementation. The studies’ high heterogeneity avoided meta-analysis. Conclusion: Notwithstanding all limitations, the promising effects of omega-3 supplementation presented in two six-month studies encourage performing RCT with better-defined treatment protocols and greater methodological rigor.     

Impact of blood source and component manufacturing on neurotrophin content and in vitro cell wound healing

BackgroundWe evaluated neurotrophin (NF) levels and their impact on in vitro cell wound healing in eye drops from differently prepared blood sources (cord blood [CB], and peripheral blood [PB]) in the same donor, to avoid intrasubject biological variability.Materials and methodsTwenty healthy adult donor PB samples, and twenty CB samples acquired at the time of delivery were processed to obtain serum (S), platelet-rich plasma (PRP), platelet-poor plasma (PPP), and S retrieved from PRP after activation with Ca-gluconate (PRP-R). The levels of brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), glial-derived neurotrophic factor (GDNF), fibroblast growth factor (FGF), and epidermal growth factor (EGF) were assessed with a Luminex xMAP (Luminex Corporation), and by using multikine kits from R&D system, and were statistically analysed in the eight different preparations. The impact of S, PRP, PPP, PRP-R from both sources on a cell line responding to NF supplementation (MIO-M1, UCL Institute of Ophthalmology, London, UK) was tested with a scratch wound assay, and analysed by IncuCyte S3 equipment.ResultsAll the preparations from CB showed higher NF levels, except for BDNF where no difference was found as compared to PB. PRP showed higher NF levels with respect to S, PPP and PRP-R in this decreasing order. Younger donors in PB contributed with higher NF levels. The scratch assay showed different cell migration results, with a complete wound closure only recorded with the supplementation of CB-S, and a progressive reduction by using PRP, PRP-R, and PPP from both sources.DiscussionProtocols of preparation and choice of blood source determine different NF levels in the final products. The therapeutic use of a natural neurotrophin pool from blood sources might have a clinical impact in several different settings. Efforts are needed to standardise the manufacturing and the product content in order to establish and modulate the posology of the final supplementation.     

Patellofemoral pain: an update on diagnostic and treatment options

Patellofemoral pain is a frequent and often challenging clinical problem. It affects females more than males and includes many different pathologic entities that result in pain in the anterior aspect of the knee. Diagnosis of the specific cause of pain can be difficult and requires assessment of lower extremity strength, alignment, and range of motion, as well as specific patella alignment, tracking, and mobility. The treatment for patellofemoral pain is usually conservative with anti-inflammatory medications, activity modification, and a specific physical therapy program focusing on strengthening and flexibility. Infrequently, surgical treatment may be indicated after a non-operative program fails. The outcomes of surgical management may include debridement, lateral release, and realignment of the extensor mechanism to unload the patellofemoral articulation are favorable.     

Haeme oxygenase-1 promoter polymorphism is an independent prognostic marker of gastrointestinal stromal tumour

Aims:  Gastrointestinal stromal tumours (GISTs) display genetic alterations on chromosome 22. GTn repeat (GTn) length polymorphism in the promoter of haeme oxygenase-1 gene ( HMOX-1 ) is located on chromosome 22 and associated with malignant growth. The aim was to investigate the role of HMOX-1 promoter polymorphism in GIST patients.
Methods and results:  Tumour and corresponding healthy tissue DNA of 44 patients who underwent surgical resection of GIST were analysed by polymerase chain reaction, capillary electrophoresis and DNA sequencing. GTn polymorphism was classified into short (S) and long (L) allele. There was no difference detected in GTn genotype between tumour and healthy tissue DNA. Short GTn allele (SGTn) was significantly associated with metastatic disease, higher tumour recurrence rates and high risk GIST (consensus criteria 2001). Furthermore, SGTn allele carriers had significantly shorter disease-free and overall survival (log rank test, P  < 0.0001). On multivariate Cox regression analysis, GTn polymorphism was identified as an independent prognostic factor for survival ( P  = 0.001).
Conclusions:  HMOX-1 promoter GTn polymorphism is a potential prognostic marker and may help to allocate patients to different risk groups, customized therapy and follow-up. Haeme oxygenase-1 could represent an important candidate gene in the pathogenesis and growth of GIST.