Is there a ‘Basque’ profile regarding autosomal recessive deficiencies of coagulation factors?*

When excluding haemophilia and von Willebrand disease, coagulation factors deficiencies constitute rare autosomal recessive disorders (<1 in 500,000) of less precisely defined epidemiology. We have reported herein the distribution of these entities in the French Basque Country, a genetic isolate of very old individualization with peculiar biological specificities. The prevalence of these disorders was markedly high, especially, as already shown, factor XI deficiency. This unusual profile needs to be discussed in the view of population genetics.     

Infection Control Citations in Nursing Homes: Compliance and Geographic Variability

ObjectivesTo report the initial compliance with new infection control regulations and geographic disparities in nursing homes (NHs) in the United States.DesignRetrospective cohort study from November 27, 2017 to November 27, 2019.Setting and ParticipantsIn total, 14,894 NHs in the continental United States comprising 26,201 inspections and 176,841 deficiencies.MethodsWe measured the cumulative incidence of receiving F880: Infection Prevention and Control deficiencies, geographic variability of F880 citations across the United States, and the scope and severity of the infection control deficiencies.ResultsA total of 6164 NHs (41%) in the continental United States received 1 deficiency for F880, and 2300 NHs (15%) were cited more than once during the 2-year period. Geographic variation was evident for F880 deficiencies, ranging from 20% of NHs in North Carolina to 79% of NHs in West Virginia. Between 0% (Vermont) and 33% (Michigan) of states’ NHs were cited multiple times over 2 years. Facilities receiving 2 or more F880 deficiencies were more reliant on Medicaid, for-profit, and served more acute residents. Infection Prevention and Control deficiencies were of similar severity but of greater scope in NHs that were cited multiple times.Conclusions and ImplicationsAs the coronavirus disease 2019 pandemic challenges hospitals with an increased surge of patients from the community, NHs will be asked to accept convalescing patients who were previously infected with the virus. NHs will need to rely on infection control practices to mitigate the effects of the virus in their facilities. Particular attention to NHs that have fared poorly with repeat infection control practices deficiencies might be a good first step to improving care overall and preventing downstream morbidity and mortality among the highest-risk patients.     

The chaperone‐like sodium phenylbutyrate improves factor IX intracellular trafficking and activity impaired by the frequent p.R294Q mutation

Essentials

• Missense mutations often impair protein folding, and thus intracellular trafficking and secretion.
• Cellular models of severe type I hemophilia B were challenged with chaperone‐like compounds.
• Sodium phenylbutyrate improved intracellular trafficking and secretion of the frequent p.R294Q.
• The increased coagulant activity levels (～3%) of p.R294Q would ameliorate the bleeding phenotype.

Summary

Background

Missense mutations often impair protein folding and intracellular processing, which can be improved by small compounds with chaperone‐like activity. However, little has been done in coagulopathies, where even modest increases of functional levels could have therapeutic implications.

Objectives

To rescue the expression of factor IX (FIX) variants affected by missense mutations associated with type I hemophilia B (HB) through chaperone‐like compounds.

Methods

Expression studies of recombinant (r)FIX variants and evaluation of secreted levels (ELISA), intracellular trafficking (immunofluorescence) and activity (coagulant assays) before and after treatment of cells with chaperone‐like compounds.

Results

As a model we chose the most frequent HB mutation (p.R294Q, ~100 patients), compared with other recurrent mutations associated with severe/moderate type I HB. Immunofluorescence studies revealed retention of rFIX variants in the endoplasmic reticulum and negligible localization in the Golgi, thus indicating impaired intracellular trafficking. Consistently, and in agreement with coagulation phenotypes in patients, all missense mutations resulted in impaired secretion (< 1% wild‐type rFIX). Sodium phenylbutyrate (NaPBA) quantitatively improved trafficking to the Golgi and dose dependently promoted secretion (from 0.3 ± 0.1% to 1.5 ± 0.3%) only of the rFIX‐294Q variant. Noticeably, this variant displayed a specific coagulant activity that was higher (~2.0 fold) than that of wild‐type rFIX in all treatment conditions. Importantly, coagulant activity was concurrently increased to levels (3.0 ± 0.9%) that, if achieved in patients, would ameliorate the bleeding phenotype.

Conclusions

Altogether, our data detail molecular mechanisms underlying type I HB and candidate NaPBA as affordable ‘personalized’ therapeutics for patients affected by the highly frequent p.R294Q mutation, and with reduced access to substitutive therapy.

     

Approaches to patients with variants in RAG genes: from diagnosis to timely treatment

ABSTRACT

Introduction: Patients with primary immunodeficiency secondary to abnormal recombinase activating genes (RAG) can present with broad clinical phenotypes ranging from early severe infections to autoimmune complications and inflammation. Immunological phenotype may also vary from T^?B^? severe combined immunodeficiency to combined immunodeficiency or antibody deficiencies with near-normal T and B cell counts and even preserved specific antibody response to pathogens. It is not uncommon that RAG variants of uncertain significance are identified by serendipity during a broad genetic screening process and pathogenic RAG variants are increasingly recognized among all age groups, including adults. Establishing the pathogenicity and clinical relevance of novel RAG variants can be challenging since RAG genes are highly polymorphic. This review paper aims to summarize clinical phenotypes of RAG deficiencies and provide practical guidance for confirming the direct link between specific RAG variants and clinical disease. Lastly, we will review the current understanding of treatment option for patients with varying severity of RAG deficiencies.

Area covered: This review discusses the different phenotypes and immunological aspects of RAG deficiencies, the diagnosis dilemma facing clinicians, and an overview of current and advancement in treatments.

Expert opinion: A careful analysis of immunological and clinical data and their correlation with genetic findings helps to determine the significance of the genetic polymorphism. Advances in functional assays, as well as anti-cytokine antibodies, make it easier to resolve the diagnostic dilemma.     

The PFA‐100® does not predict delta‐granule platelet storage pool deficiencies

Summary.  There are no published reports investigating the ability of the platelet function analyzer (PFA‐100^®) to detect the presence of delta‐granule platelet storage pool deficiencies (δ‐PSPD), a common mild bleeding disorder. Prior studies of the PFA‐100^® and congenital platelet disorders have been limited by small numbers of patients with a variety of disorders. We examined PFA‐100^® results in a large paediatric patient population diagnosed specifically with δ‐PSPD, and determined the relationship between PFA‐100^® and platelet electron microscopy (the gold standard for diagnosis). This study is a retrospective review of patients <19 years of age diagnosed with δ‐PSPD at Nationwide Children’s Hospital from 2008 to 2010. To examine the correlation between PFA‐100^® and average number of granules per platelet we used Spearman’s Rho as a non‐parametric measure of dependence. A total of 105 patients diagnosed with δ‐PSPD were included, of which 99 patients underwent PFA‐100^® testing. Of those tested 46% had at least one abnormal closure time, whereas 16% had abnormal results for both cartridges. We found no statistical correlation between C‐EPI closure time and average number of granules per platelet (ρ= ?0.0095, P‐value = 0.9328), nor between C‐ADP closure time and the average number of granules (ρ = 0.0315, P‐value = 0.7798). The PFA‐100^®, a widely used screening test for suspected bleeding disorders, did not correlate with presence or severity of δ‐PSPD as determined by platelet electron microscopy. When evaluating patients with suspected bleeding disorders, PFA‐100^® alone cannot be used to rule out the presence of a δ‐PSPD.     

Illustration of the Importance of Adjustment for within- and between-Person Variability in Dietary Intake Surveys for Assessment of Population Risk of Micronutrient Deficiency/Excess Using an Example Data Set

Nutrition intervention decisions should be evidence based. Single 24-h recalls are often used for measuring dietary intake in large dietary studies. However, this method does not consider the day-to-day variation in populations’ diets. We illustrate the importance of adjustment of single 24-h recall data to remove within-person variation using the National Cancer Institute method to calculate usual intake when estimating risk of deficiency/excess. We used an example data set comprising a single 24-h recall in a total sample of 1326 1–<10-year-old children, and two additional recalls in a sub-sample of 11%, for these purposes. Results show that risk of deficiency was materially overestimated by the single unadjusted 24-h recall for vitamins B12, A, D, C and E, while risk of excess was overestimated for vitamin A and zinc, when compared to risks derived from usual intake. Food sources rich in particular micronutrients seemed to result in overestimation of deficiency risk when intra-individual variance is not removed. Our example illustrates that the application of the NCI method in dietary surveys would contribute to the formulation of more appropriate conclusions on risk of deficiency/excess in populations to advise public health nutrition initiatives when compared to those derived from a single unadjusted 24-h recall.     

健脾益肺膏方治疗小儿反复呼吸道感染肺脾两虚、卫表不固证的临床疗效分析

目的观察健脾益肺膏方治疗小儿反复呼吸道感染(RRTI)肺脾两虚、卫表不固证的临床疗效,探析其运用于小儿RRTI预后的可行性。方法将84例RRTI肺脾两虚、卫表不固证患儿随机分为治疗组和对照组,每组42例。治疗组患儿给予健脾益肺膏方口服治疗,对照组给予脾氨肽口服冻干粉口服治疗,疗程为3个月。观察2组患儿治疗前后血中免疫球蛋白IgG、IgA、IgM水平的变化情况,并评价2组的临床疗效及安全性。结果(1)治疗3个月后,治疗组总有效率为95.24%(40/42),对照组为76.19%(32/42);治疗组疗效明显优于对照组,差异有统计学意义(P<0.05)。(2)治疗后,2组患儿的血中IgG、IgA和IgM水平均较治疗前明显提高(P<0.05),且治疗组对患儿血中IgG、IgA和IgM水平的作用均明显优于对照组,差异均有统计学意义(P<0.05)。(3)治疗组的不良反应发生率为2.38%(1/42),对照组为7.14%(3/42),组间比较,差异无统计学意义(P>0.05)。结论健脾益肺膏方治疗小儿RRTI肺脾两虚、卫表不固证疗效确切,可有效改善患儿临床症状,提高患儿免疫功能,且具有较高的安全性,可用于小儿RRTI的临床预后治疗。     

Dietary Habits of a Group of Children with Crohn’s Disease Compared to Healthy Subjects: Assessment of Risk of Nutritional Deficiencies through a Bromatological Analysis

Diet is a matter of interest in the pathogenesis and management of Crohn’s Disease (CD). Little is known about CD children’s dietary habits. Our aim was assessing the quality and the amount of nutrient intake in a group of CD pediatric patients. Data were compared with those of healthy subjects (HS). In total, 20 patients (13 males) and 48 HS (24 males) aged 4–18 years were provided with a food diary to fill out for one week. Winfood software performed the bromatological analysis, providing data about intakes of proteins and amino acids, fatty acids, carbohydrates, cholesterol, fibers, minerals, vitamins, and polyphenols. Estimates of the antioxidant activity of foods and of the dietetic protein load were also calculated. The diet of CD patients was poorer in fibers, polyphenols, vitamin A, beta-carotene, and fatty acids, and richer in animal proteins, vitamin B12, and niacin. PRAL was higher in CD patients’ diets, while ORAC was higher in HS. No significant differences were observed in carbohydrate and other macro- and micronutrient consumptions. CD dietary habits seem to reflect the so-called Western diet, possibly involved in CD pathogenesis. Furthermore, analysis of dietary habits allows for prevention of nutritional deficiencies and timely correction through education and supplementation.     

Nutritional status and intestinal parasites among young children from pastoralist communities of the Ethiopian Somali region

Pastoralist children in the Ethiopian Somali Regional State (ESRS) are at high risk for undernutrition and intestinal parasitic infections (IPIs). We assessed the nutritional status and its association with IPIs in 500 children <5 years of age in a clustered cross‐sectional study in Adadle district, ESRS. Stool samples were microscopically examined for IPIs and biomarkers for iron and vitamin A status, anthropometry, and food variety score (FVS) were assessed. Median (interquartile range [IQR]) FVS was 2.0 (2.0, 4.0), and 35% of children were exclusively breastfed up to age 6 months. Prevalence of stunting, wasting, underweight and mid‐upper arm circumference (MUAC) <12.5 cm was 30, 34, 40, and 16%, respectively. Median (IQR) haemoglobin, ferritin, and retinol‐binding protein concentrations were 9.5 g dL^‐1 (8.2, 10.9), 6.2 μg L^‐1 (4.0, 10.2), and 0.8 μmol L^?1 (0.67, 0.91), respectively. Prevalence of anaemia, iron, and vitamin A deficiency was 75, 91, and 30%, respectively. IPIs' prevalence was 47%; the most prevalent IPIs were Giardia lamblia (22%) and Ascaris lumbricoides (15%). Giardial infections but not A. lumbricoides increased the risk for MUAC <12.5 cm (adjusted odds ratio [aOR]: 3.50, 95% confidence interval [CI] [2.21, 5.54]). The odds for anaemia were 97% (aOR: 0.03, 95% CI [0.03, 0.07]) and 89% (aOR: 0.11, 95% CI [0.11, 0.23]) less for children with FVS >2 or with exclusive breastfeeding up to 6 months, respectively. Undernutrition and IPIs are alarmingly high in <5 years of age children in ESRS. Giardial infections and low nutritional adequacy of the diet seem to be major contributing factors to the precarious nutritional status and should be addressed by appropriate interventions.     

Infant anaemia is associated with infection,low birthweight and iron deficiency in rural Bangladesh

Aim: To estimate the prevalence of infant anaemia and its association with iron deficiency, growth, infection and other micronutrient deficiencies. Methods: Using data from MINIMat, a randomized maternal food and micronutrient supplementation trial, we assessed the associations between anaemia (haemoglobin < 105 g/L) in 580 infants at 6 months and deficiencies of iron, vitamin A, vitamin B12, zinc and folate, infection and anthropometric indices. Variables associated with anaemia in bivariate analyses were evaluated in logistic regression models, adjusting for potential confounders. Results: Anaemia was found in 46% of the infants, and among these, 28% had iron deficiency (plasma ferritin <9 μg/L). Elevated C‐reactive protein (>10mg/L) (OR = 2.7, 95% CI: 1.6, 4.7), low birthweight (OR = 2.3, 95% CI: 1.5, 3.5) and iron deficiency (OR = 2.2, 95% CI: 1.4, 3.6) were independently associated with increased risk for anaemia. We also observed a seasonal variation in anaemia not mediated through the other factors studied. Conclusion: In a cohort in rural Bangladesh, anaemia at age 6 months was common and associated with infection, low birthweight and iron deficiency.