Explore the vast range of titles available.

Vascular Ehlers Danlos Syndrome (vEDS) is a connective tissue disorder caused by COL3A1 mutations for which there are no treatments due to a limited understanding of underlying mechanisms. We aimed to identify the molecular insults of mutations, focusing on collagen folding, to establish if targeting protein folding represents a potential therapeutic approach. Analysis of two novel COL3A1 glycine mutations, G189S and G906R, in primary patient fibroblast cultures revealed secretion of misfolded collagen III and intracellular collagen retention leading to lower extracellular collagen levels. This was associated with matrix defects, endoplasmic reticulum (ER) stress, reduced cell proliferation and apoptosis. The ER stress was mediated by activation of IRE1 and PERK signalling arms with evidence of allelic heterogeneity. To establish if promoting ER protein folding capacity or protein degradation represents novel therapeutic avenues, we investigated the efficacy of FDA-approved small molecules. The chemical chaperone 4-phenylbutyric acid (PBA) rescued the ER stress and thermostability of secreted collagen leading to reduced apoptosis and matrix defects, and its efficacy was influenced by duration, dosage and allelic heterogeneity. Targeting protein degradation with carbamazepine (CBZ), or PBA-CBZ in combination did not increase treatment efficacy. These data establish that ER stress is a molecular mechanism in vEDS that can be influenced by the position of COL3A1 mutation. It combines with matrix defects due to reduced collagen III levels and/or mutant protein secretion to vEDS pathogenesis. Targeting protein folding using FDA-approved chemical chaperones represents a putative mechanism-based therapeutic approach for vEDS that can rescue intra- and extracellular defects.

DTaP-IPV-Hib-HepB is a fully-liquid, hexavalent combination vaccine (Vaxelis™) approved for vaccination against diphtheria, tetanus, pertussis, poliomyelitis, hepatitis B, and invasive disease due to Haemophilus influenzae type b (Hib). Hib capsular polysaccharide, polyribosylribitol phosphate (PRP), is conjugated to Neisseria meningitidis outer membrane protein complex (OMPC). Safety and immunogenicity of DTaP-IPV-Hib-HepB were evaluated in 6 Phase III clinical studies including > 5,200 children. Studies included vaccination schedules in the United States (2, 4, 6 months of age) and Europe (2, 3, 4, 12 months of age and 2,4,11-12 months of age). Data pertaining to anti-PRP responses of DTaP-IPV-Hib-Hep B compared to control vaccines from 5 Phase III studies are summarized. Post-infant series, the percentage of participants that achieved protective antibody thresholds for PRP (anti-PRP titer ≥ 0.15 μg/mL and ≥ 1.0 μg/mL, respectively) were higher in DTaP-IPV-Hib-HepB recipients compared to recipients who received control vaccines. A high level of protective responses (96.6% at ≥ 0.15 μg/mL [95% CI:94.8, 97.9%]; 72.9% at ≥ 1.0 μg/mL [95% CI:69.2,76.4%]) were seen post-dose 2 of the 2 + 1 vaccination schedule and met superiority criteria over comparator, p-value < 0.001. In the same schedule, prior to administration of the toddler dose (in the second year of life), anti-PRP titers were higher in DTaP-IPV-Hib-HepB recipients (91.4% at ≥ 0.15 μg/mL; 46.8% at ≥ 1.0 μg/mL) as compared to recipients who received control vaccines (63.4% at ≥ 0.15 μg/mL; 17.1% at ≥ 1.0 μg/mL). One-month post-toddler dose, high levels of anti-PRP titers were achieved in both DTaP-IPV-Hib-HepB recipients (99.8% at ≥ 0.15 μg/mL; 96.6% at ≥ 1.0 μg/mL) and recipients who received control vaccines (99.5% at ≥ 0.15 μg/mL; 94.9% at ≥ 1.0 μg/mL). These results support that DTaP-IPV-Hib-HepB induces a robust and sustained early Hib response. During the high-risk period for Hib disease after the infant vaccine and prior to the toddler dose; >90% of recipients maintained superior protective anti-PRP levels compared to control.

IntroductionWe aimed to determine the impact of antenatal interventions to optimise maternal nutrition and infection management on birth outcomes in Ethiopia.MethodsWe conducted a pragmatic, open-label, 2×2 factorial randomised clinical effectiveness study among pregnant women enrolled <24 weeks gestation in 12 rural health centres in Amhara, Ethiopia. Eligible health centres were randomised to deliver an enhanced nutrition package (ENP) (iron-folic acid, iodised salt and targeted micronutrient fortified balanced energy protein (BEP) supplementation for undernourished women) or routine nutrition care (iron-folic acid only). Individual women were randomised to receive an enhanced infection management package (EIMP) (genitourinary tract infection screening-treatment and enhanced deworming) or routine infection care (syndromic management). The primary outcomes were birth weight and length; secondary outcomes were gestational age, preterm delivery, small-for-gestational-age, low birth weight, stillbirth, newborn weight-for-age and length-for-age z-scores, newborn head circumference, and maternal anemia. Analysis was intention to treat.ResultsFrom August 2020 to December 2021, 2392 women were randomised (604 ENP+EIMP, 600 ENP alone, 593 EIMP alone and 595 neither package) and followed until June 2022, with 2170 pregnancy outcomes analysed (565 ENP+EIMP, 549 ENP, 525 EIMP, 531 neither). In the ENP arm, 427 (36%) women were eligible for BEP and consumed on average 74 days. The prevalence of genitourinary tract infection was low (4.9%), while parasitic stool infections were common (31%). There was no difference in birth weight (ENP vs not-ENP: adjusted mean difference −4 g (−83 to 75); EIMP vs not-EIMP: 18 g (−35 to 70); ENP+EIMP vs neither: 14 g (−81 to 109)) or birth length (ENP: −0.3 cm (−1.1 to 0.5); EIMP: 0.2 cm (−0.1 to 0.5); ENP+EIMP: −0.1 cm (−1.2 to 1.1)) between study arms. In the ENP+EIMP group, the stillbirth rate was lower compared with the arm receiving neither package (7.1/1000 vs 24.7/1000 births; adjusted relative risk: 0.29 (0.09 to 0.94)). The packages did not significantly affect other secondary outcomes.ConclusionsIn this pragmatic study implemented within the Ethiopian health system, enhanced nutrition and infection packages did not affect birth weight or length. While stillbirth rates were lower in the group receiving both packages, these findings need to be supported by additional studies.Trial registration number ISRCTN15116516.

BackgroundThe management of a hemodynamically significant patent ductus arteriosus (hsPDA) associated with cardiomegaly and at least more than 1.5 mm in preterm infants is still a controversial topic. Previously, prophylaxis with ibuprofen was practiced in some units Nowadays, a conservative strategy with the use of diuretics and fluid restriction is considered a treatment option, alongside medical treatment with cyclo-oxygenase inhibitors (eg. Ibuprofen,indomethacin), paracetamol and surgery. The impact of the these practices have not been well studied.ObjectivesWe aim to determine the impact of hsPDA on the short term growth and cognitive outcomes of very low birth weight (VLBW) infants managed at a tertiary unit in Singapore from 2014 to 2018.MethodsA retrospective study on growth and cognitive outcomes was conducted on patients recruited from the outpatient follow-up clinic. Baseline neonatal demographics, treatment of hsPDA and short term neonatal morbidities were collected. Information on postnatal growth, health outcomes and cognitive testing scores were collected as well. Categorical data were compared with Chi squared test between those with medical or surgery treatment and those with conservative treatment.Continuous data with normal distribution was reported with means and Student t test was used for analysis. Those with skewed distribution was reported with medians and Mann-Whitney test was performed.Results89 children were recruited at a median age of 34.5 (IQR 18–52) months, with equal gender distribution. Interestingly, infants (n=61) who had hsPDA requiring treatment were more mature (29.9 vs 27.5 weeks) and heavier 1305 g vs 985 g (P < 0.01) at birth compared to VLBWs with conservative treatment (n=21). Despite their maturity and also larger weight, those who required treatment were more likely to have been mechanically ventilated 66.7% vs 33.3% (p < 0.01). As such, those who required PDA treatment had increased incidence of chronic lung disease (CLD) at 36 weeks (83.8% vs 60.8%%,p=0.04), increased length of stay (79.5 vs 59.0 days, P <0.01) and requirement of inhaled medications on follow-up. Growth failure of VLBWs with conservative treatment was evident until 6 months corrected age. Median cognitive scores were not statistically different, 97(IQR 85–105) vs 92 (IQR 81–101) when measured at ages 2–5 years. No differences were seen in the hearing loss or cerebral palsy rates. No association between PDA treatment and CLD were identified with a low cognitive score of less than 85.ConclusionsIn our small cohort, the presence of a hemodynamically significant PDA requiring treatment was associated with a higher incidence of CLD needing long term medication but no impairment of cognition and growth at follow-up.

Overactivation of calcium-activated neutral protease (calpain) has been implicated in the pathophysiology of several degenerative conditions, including stroke, myocardial ischemia, neuromuscular degeneration, and cataract formation. Alpha-mercaptoacrylate derivatives (exemplified by PD150606), with potent and selective inhibitory actions against calpain, have been identified. PD150606 exhibits the following characteristics: (i) Ki values for μ - and m-calpains of 0.21 μ M and 0.37 μ M, respectively, (ii) high specificity for calpains relative to other proteases, (iii) uncompetitive inhibition with respect to substrate, and (iv) it does not shield calpain against inactivation by the active-site inhibitor trans-(epoxysuccinyl)-L-leucyl-amido-3-methylbutane, suggesting a nonactive site action for PD150606. The recombinant calcium-binding domain from each of the large or small subunits of μ -calpain was found to interact with PD150606. In low micromolar range, PD150606 inhibited calpain activity in two intact cell systems. The neuroprotective effects of this class of compound were also demonstrated by the ability of PD150606 to attenuate hypoxic/hypoglycemic injury to cerebrocortical neurons in culture and excitotoxic injury to Purkinje cells in cerebellar slices.