Burriscraig5248

he largest international real-world data set of people with MS with suspected/confirmed COVID-19 confirms that the use of anti-CD20 medication (both ocrelizumab and rituximab), as well as male sex, older age, progressive MS, and higher disability are associated with more severe course of COVID-19.

In a phase 1 amyotrophic lateral sclerosis (ALS) study, autologous infusions of expanded regulatory T-lymphocytes (Tregs) combined with subcutaneous interleukin (IL)-2 were safe and well tolerated. Treg suppressive function increased and disease progression stabilized during the study. The present study was conducted to confirm the reliability of these results.

Participants with ALS underwent leukapheresis, and their Tregs were isolated and expanded in a current Good Manufacturing Practice facility. Seven participants were randomly assigned in a 11 ratio to receive Treg infusions (1 × 10

cells/kg) IV every 4 weeks and IL-2 (2 × 10

IU/m

) injections 3 times/wk or matching placebo in a 24-week randomized controlled trial (RCT). Six participants proceeded into a 24-week dose-escalation open-label extension (OLE). Two additional participants entered directly into the OLE. The OLE included dose escalation of Treg infusions to 2 × 10

cells/kg and 3 × 10

cells/kg at 4-week intervals.

The Treg/IL-2 treith higher Treg suppressive function. CC-115 in vivo During the OLE, 6 of 8 participants showed slow to no progression. The 2 of 8 rapid progressors had elevated markers of oxidative stress and inflammation, which may help delineate responsiveness to therapy. Whether Treg/IL-2 treatments can slow disease progression requires a larger clinical study (ClinicalTrials.gov number, NCT04055623).

This study provides Class IV evidence that Treg infusions and IL-2 injections are safe and effective for patients with ALS.

This study provides Class IV evidence that Treg infusions and IL-2 injections are safe and effective for patients with ALS.Group 2 innate lymphoid cells (ILC2s) have been implicated in both physiologic tissue remodeling and allergic pathology, yet the niche signaling required for ILC2 properties is poorly understood. Here, we show that an axonal guidance cue semaphorin 6D (Sema6D) plays critical roles in the maintenance of IL-10-producing ILC2s. Sema6d -/- mice exhibit a severe steady-state reduction in ILC2s in peripheral sites such as the lung, visceral adipose tissue, and mesentery. Interestingly, loss of Sema6D results in suppressed alarmin-driven type 2 cytokine production but increased IL-10 production by lung ILC2s both in vitro and in vivo. Consequently, Sema6d -/- mice are resistant to the development of allergic lung inflammation. We further found that lung mesenchymal cells highly express Sema6D, and that niche-derived Sema6D is responsible for these phenotypes through plexin A1. Collectively, these findings suggest that niche-derived Sema6D is implicated in physiological and pathological characteristics of ILC2s.

Hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant condition characterised by recurrent epistaxis, telangiectatic lesions in the skin and mucosal membranes, and arteriovenous malformations (AVMs) in various organs. In 3%-5% of patients, HHT is caused by pathogenic germline variants (PVs) in

, and these patients often have additional symptoms of juvenile polyposis syndrome and thoracic aneurysms. The phenotypic spectrum of

-associated HHT is less known, including the penetrance and severity of HHT. We aimed to investigate the phenotypic spectrum of HHT manifestations in Danish patients with PVs in

and compare the findings with current literature.

The study is a retrospective nationwide study with all known Danish patients with PVs in

. In total, 35 patients were included. The patients were identified by collecting data from genetic laboratories, various databases and clinical genetic departments across the country. Clinical information was mainly collected from the Danish HHT-Centre at Odense University Hospital.

Twenty-nine patients with PVs in

(83%) were seen at the HHT-Centre. Seventy-six per cent of these fulfilled the Curaçao criteria, 86% experienced recurrent epistaxis and 83% presented with telangiectatic lesions at different anatomical localisations. Almost 60% had AVMs, mainly pulmonary and hepatic, while none was found to have cerebral AVMs. Fifteen per cent had thoracic aortic abnormalities.

We present a nationwide study of one of the largest populations of patients with PVs in

that has systematically been examined for HHT manifestations. The patients presented the full spectrum of HHT-related manifestations and the majority fulfilled the Curaçao criteria.

We present a nationwide study of one of the largest populations of patients with PVs in SMAD4 that has systematically been examined for HHT manifestations. The patients presented the full spectrum of HHT-related manifestations and the majority fulfilled the Curaçao criteria.

Pathogenic variants (PV) of

are found in families fulfilling criteria for hereditary diffuse gastric cancer (HDGC) but no risk estimates were available until now. The aim of this study is to evaluate diffuse gastric cancer (DGC) risks for carriers of germline

PV.

Data from published CTNNA1 families were updated and new families were identified through international collaborations. The cumulative risk of DGC by age for PV carriers was estimated with the genotype restricted likelihood (GRL) method, taking into account non-genotyped individuals and conditioning on all observed phenotypes and genotypes of the index case to obtain unbiased estimates. A non-parametric (NP) and the Weibull functions were used to model the shape of penetrance function with the GRL. Kaplan-Meier incidence curve and standardised incidence ratios were also computed. A 'leave-one-out' strategy was used to evaluate estimate uncertainty.

Thirteen families with 46 carriers of PV were included. The cumulative risks of DGC at 80 years for carriers of

PV are 49% and 57%, respectively with the Weibull GRL and NP GRL methods. Risk ratios to population incidence reach particularly high values at early ages and decrease with age. At 40 years, they are equal to 65 and 833, respectively with the Weibull GRL and NP GRL.

This is the largest series of

families that provides the first risk estimates of GC. These data will help to improve management and surveillance for these patients and support inclusion of

in germline testing panels.

This is the largest series of CTNNA1 families that provides the first risk estimates of GC. These data will help to improve management and surveillance for these patients and support inclusion of CTNNA1 in germline testing panels.

Monogenic disorders are estimated to account for 10%-12% of patients with kidney failure. We report the unexpected finding of an unusual uromodulin

variant in multiple pedigrees within the British population and demonstrate a shared haplotype indicative of an ancestral variant.

Probands from 12 apparently unrelated pedigrees with a family history of kidney failure within a geographically contiguous UK region were shown to be heterozygous for a pathogenic variant of

c.278_289delTCTGCCCCGAAG insCCGCCTCCT.

A total of 88 clinically affected individuals were identified, all born in the UK and of white British ethnicity. 20 other individuals with the variant were identified in the UK 100,000 Genomes (100K) Project and 9 from UK Biobank (UKBB). A common extended haplotype was present in 5 of the UKBB individuals who underwent genome sequencing which was only present in <1 in 5000 of UKBB controls. Significantly, rare variants (<1 in 250 general population) identified within 1 Mb of the

variant by genome sequencing were detected in all of the 100K individuals, indicative of an extended shared haplotype.

Our data confirm a likely founder

variant with a wide geographical distribution within the UK. It should be suspected in cases of unexplained familial nephropathy presenting in patients of white British ancestry.

Our data confirm a likely founder UMOD variant with a wide geographical distribution within the UK. It should be suspected in cases of unexplained familial nephropathy presenting in patients of white British ancestry.

To establish the most effective and best tolerated dose of caffeine citrate for the prevention of intermittent hypoxaemia (IH) in late preterm infants.

Phase IIB, double-blind, five-arm, parallel, randomised controlled trial.

Neonatal units and postnatal wards of two tertiary maternity hospitals in New Zealand.

Late preterm infants born at 34

-36

weeks' gestation, recruited within 72 hours of birth.

Infants were randomly assigned to receive a loading dose (10, 20, 30 or 40 mg/kg) followed by 5, 10, 15 or 20 mg/kg/day equivolume enteral caffeine citrate or placebo daily until term corrected age.

IH (events/hour with oxygen saturation concentration ≥10% below baseline for ≤2 min), 2 weeks postrandomisation.

132 infants with mean (SD) birth weight 2561 (481) g and gestational age 35.7 (0.8) weeks were randomised (24-28 per group). Caffeine reduced the rate of IH at 2 weeks postrandomisation (geometric mean (GM) 4.6, 4.6, 2.0, 3.8 and 1.7 events/hour for placebo, 5, 10, 15 and 20 mg/kg/day, respectively), with differences statistically significant for 10 mg/kg/day (GM ratio (95% CI] 0.39 (0.20 to 0.76]; p=0.006) and 20 mg/kg/day (GM ratio (95% CI] 0.33 (0.17 to 0.68]; p=0.003) compared with placebo. The 20 mg/kg/day dose increased mean (SD) pulse oximetry oxygen saturation (SpO

) (97.2 (1.0) vs placebo 96.0 (0.8); p<0.001), and reduced median (IQR) percentage of time SpO

<90% (0.5 (0.2-0.8) vs 1.1 (0.6-2.4); p<0.001) at 2 weeks, without significant adverse effects on growth velocity or sleeping.

Caffeine reduces IH in late preterm infants at 2 weeks of age, with 20 mg/kg/day being the most effective dose.

ACTRN12618001745235.

ACTRN12618001745235.

Mechanisms of non-invasive high-frequency oscillatory ventilation (nHFOV) in preterm infants are unclear. We aimed to compare lung volume changes during apnoeas in preterm infants on nHFOV and nasal continuous positive airway pressure (nCPAP).

Analysis of electrical impedance tomography (EIT) data from a randomised crossover trial comparing nHFOV with nCPAP in preterm infants at 26-34 weeks postmenstrual age. EIT data were screened by two reviewers to identify apnoeas ≥10 s. End-expiratory lung impedance (EELI) and tidal volumes (V

) were calculated before and after apnoeas. Oxygen saturation (SpO

) and heart rate (HR) were extracted for 60 s after apnoeas.

In 30 preterm infants, 213 apnoeas were identified. During apnoeas, oscillatory volumes were detectable during nHFOV. EELI decreased significantly during apnoeas (∆EELI nCPAP -8.0 (-11.9 to -4.1) AU/kg, p<0.001; ∆EELI nHFOV -3.4 (-6.5 to -0.3), p=0.03) but recovered over the first five breaths after apnoeas. Compared with before apnoeas, V

was increased for the first breath after apnoeas during nCPAP (∆V

7.5 (3.1 to 11.2) AU/kg, p=0.001). Falls in SpO

and HR after apnoeas were greater during nCPAP than nHFOV (mean difference (95% CI) SpO

3.6% (2.7 to 4.6), p<0.001; HR 15.9 bpm (13.4 to 18.5), p<0.001).

Apnoeas were characterised by a significant decrease in EELI which was regained over the first breaths after apnoeas, partly mediated by a larger V

. Apnoeas were followed by a considerable drop in SpO

and HR, particularly during nCPAP, leading to longer episodes of hypoxemia during nCPAP. Transmitted oscillations during nHFOV may explain these benefits.

ACTRN12616001516471.

ACTRN12616001516471.