Importance Severe coronavirus disease 2019 (COVID-19) can occur in younger, predominantly male, patients without preexisting medical conditions. Some individuals may have primary immunodeficiencies that predispose to severe infections caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Objective To explore the presence of genetic variants associated with primary immunodeficiencies among young patients with COVID-19. Design, Setting, and Participants Case series of pairs of brothers without medical history meeting the selection criteria of young (age Exposure Severe COVID-19. Main Outcome and Measures Results of rapid clinical whole-exome sequencing, performed to identify a potential monogenic cause. Subsequently, basic genetic and immunological tests were performed in primary immune cells isolated from the patients and family members to characterize any immune defects. Results The 4 male patients had a mean age of 26 years (range, 21-32), with no history of major chronic disease. They were previously well before developing respiratory insufficiency due to severe COVID-19, requiring mechanical ventilation in the ICU. The mean duration of ventilatory support was 10 days (range, 9-11); the mean duration of ICU stay was 13 days (range, 10-16). One patient died. Rapid clinical whole-exome sequencing of the patients and segregation in available family members identified loss-of-function variants of the X-chromosomalTLR7.In members of family 1, a maternally inherited 4-nucleotide deletion was identified (c.2129_2132del; p.[Gln710Argfs*18]); the affected members of family 2 carried a missense variant (c.2383G>T; p.[Val795Phe]). In primary peripheral blood mononuclear cells from the patients, downstream type I interferon (IFN) signaling was transcriptionally downregulated, as measured by significantly decreased mRNA expression ofIRF7,IFNB1, andISG15on stimulation with the TLR7 agonist imiquimod as compared with family members and controls. The production of IFN-γ, a type II IFN, was decreased in patients in response to stimulation with imiquimod. Conclusions and Relevance In this case series of 4 young male patients with severe COVID-19, rare putative loss-of-function variants of X-chromosomalTLR7were identified that were associated with impaired type I and II IFN responses. These preliminary findings provide insights into the pathogenesis of COVID-19.

/pdf/presence-of-genetic-variants-among-young-men-with-severe-2y02wt9l1h.pdf

Presence of Genetic Variants Among Young Men With Severe COVID-19.

Gestational diabetes mellitus (GDM) is the most common metabolic disturbance during pregnancy. The prevalence is rising and correlates with the increase in maternal obesity over recent decades. The etiology of GDM is complex, with genetic and environmental factors implicated in mechanistic and epidemiological studies. GDM begets important short- and long-term health risks for the mother, developing fetus, and offspring. This includes the high likelihood of subsequent maternal type 2 diabetes (T2DM), and possible adverse cardiometabolic phenotypes in the offspring. The most clinically and cost-effective methods of screening for GDM remain uncertain. Whilst treatments with lifestyle and pharmacological interventions have demonstrated short-term benefits, the long-term impact for the offspring of intrauterine exposure to antidiabetic medication remains unclear.

Gestational Diabetes Mellitus: Mechanisms, Treatment, and Complications.

BACKGROUND
The only treatment option for peanut allergy is strict avoidance.


OBJECTIVE
To investigate efficacy and safety of oral immunotherapy (OIT) in peanut allergy.


METHODS
Twenty-three children (age, 3.2-14.3 years) with IgE-mediated peanut allergy confirmed by positive double-blind, placebo-controlled food challenge (DBPCFC) received OIT following a rush protocol with roasted peanut for 7 days. If a protective dose of at least 0.5 g peanut was not achieved, patients continued with a long-term buildup protocol using biweekly dose increases up to at least 0.5 g peanut. A maintenance phase for 8 weeks was followed by 2 weeks of peanut avoidance and a final DBPCFC. Immunologic parameters were determined.


RESULTS
After OIT using the rush protocol, patients tolerated a median dose of only 0.15 g peanut. Twenty-two of 23 patients continued with the long-term protocol. After a median of 7 months, 14 patients reached the protective dose. At the final DBPCFC, patients tolerated a median of 1 g (range, 0.25-4 g) in comparison with 0.19 g peanut at the DBPCFC before OIT (range, 0.02-1 g). In 2.6% of 6137 total daily doses, mild to moderate side effects were observed; in 1.3%, symptoms of pulmonary obstruction were detected. OIT was discontinued in 4 of 22 patients because of adverse events. There was a significant increase in peanut-specific serum IgG(4) and a decrease in peanut-specific IL-5, IL-4, and IL-2 production by PBMCs after OIT.


CONCLUSION
Long-term OIT appears to be safe and of some benefit in many patients with peanut allergy. With an increase in threshold levels and a reduction of peanut-specific T(H)2 cytokine production, the induction of tolerance may be feasible in some patients.

Iconographies supplémentaires de l'article : Oral peanut immunotherapy in children with peanut anaphylaxis

Cerebral blood flow was studied by the arteriovenous oxygen difference method in patients with severe hypertension and in normotensive controls. The blood pressure was lowered to study the lower limit of autoregulation (the pressure below which cerebral blood flow decreases) and the pressure limit of brain hypoxia. Both limits were shifted upwards in the hypertensive patients, probably as a consequence of hypertrophy of the arteriolar walls. These findings have practical implications for antihypertensive therapy.When the blood pressure was raised some patients showed an upper limit of autoregulation beyond which an increase of cerebral blood flow above the resting value was seen without clinical symptoms. No evidence of vasospasm was found in any patient at high blood pressure. These observations may be of importance for the understanding of the pathogenesis of hypertensive encephalopathy.

Autoregulation of brain circulation in severe arterial hypertension

Noninvasive blood tests that provide information about fetal development and gestational age could potentially improve prenatal care. Ultrasound, the current gold standard, is not always affordable in low-resource settings and does not predict spontaneous preterm birth, a leading cause of infant death. In a pilot study of 31 healthy pregnant women, we found that measurement of nine cell-free RNA (cfRNA) transcripts in maternal blood predicted gestational age with comparable accuracy to ultrasound but at substantially lower cost. In a related study of 38 women (23 full-term and 15 preterm deliveries), all at elevated risk of delivering preterm, we identified seven cfRNA transcripts that accurately classified women who delivered preterm up to 2 months in advance of labor. These tests hold promise for prenatal care in both the developed and developing worlds, although they require validation in larger, blinded clinical trials.

https://science.sciencemag.org/content/sci/360/6393/1133.full.pdf

Noninvasive blood tests for fetal development predict gestational age and preterm delivery

The prevalence of gestational diabetes mellitus recurrence--effect of ethnicity and parity: a metaanalysis.

Background IgE-mediated cow's milk–allergic (IgE-CMA) patients provide a valuable model for studying the relationship between dairy intake and bone mineral density (BMD) because they are unable to consume even minor amounts of dairy foods. Objective To determine the effects of dairy restriction on BMD in young adult IgE-CMA patients. Methods A prospective observational study was conducted from July 2012 to June 2013 at the Allergy unit of the Assaf-Harofeh Medical Center. Densitometric measurements of postpubertal patients diagnosed with IgE-CMA (group I, n = 33) were compared with those of volunteers matched for age and sex without IgE-CMA (control group II, n = 24). In a second analysis, group I and II patients were compared with IgE-CMA patients who after desensitization consumed milk for 12 to 39 months before analysis (group III, n = 12). Results Densitometric measurements (average T scores and Z scores) of the hip, femoral neck, and lumbar spine of IgE-CMA patients were significantly lower than of those in the control group ( P T score below −2.5 SD, identifying a risk for osteoporosis, was found in 27% of IgE-CMA patients but in none of the controls ( P  = .0071). Calcium intake was severely reduced in allergic patients than in controls ( P P Conclusions Patients with IgE-CMA have a significant risk of reduced BMD and early osteoporosis, which appears to be reversible on milk desensitization. Adequate calcium intake is not achieved while on a nondairy diet, requiring investigation into optimal nutritional protocols for these patients.

Decreased bone mineral density in young adult IgE-mediated cow's milk-allergic patients.

The literature regarding risk factors for gestational diabetes mellitus (GDM) recurrence is inconsistent. We aimed to assess the effect sizes of risk factors of GDM recurrence. We searched electronic databases (1970-2015) and bibliographies for studies that included women with GDM (index pregnancy) who had a consecutive birth. We compared the risk factors among women with and without GDM recurrence. Differences in variables measured on a continuous scale were estimated using the weighted mean difference (WMD). The standardized mean difference (SMD) was used to rate the pooled effects. For categorical variables, the pooled odds ratio was estimated. Cochran's Q test of heterogeneity was used to choose the model for estimating the pooled effects. Fourteen cross-sectional cohort studies (63 % with sample size ≥100) were considered. Women with GDM recurrence were older (by 1.32 years; P < 0.0001), heavier (by 1.82 BMI; P = 0.013), had higher 100-g oral glucose tolerance test (OGTT) levels (Fasting: by 8.42 mg/dl, 1-h: by 13.0 mg/dl, 2-h: by 18.2 mg/dl, 3-h: by 11.3 mg/dl; P < 0.0001 for all) and higher weight gain between pregnancies (by 3.24 kg; P = 0.012). The SMD effect sizes were relatively small (between 0.3 and 0.4), but weight gain between pregnancies had a medium-large effect size (SMD = 0.8). Insulin use, multiparity, and fetal macrosomia were all associated with GDM recurrence (OR 6.3 [95 % CI 3.9-10.2], OR 1.88 [95 % CI 1.09-3.24] and OR 1.63 [95 % CI 1.25-2.13], respectively). GDM recurrence is multifactorial. Stronger risk factors include insulin use, BMI, multiparity, macrosomia, and weight gain between pregnancies.

Risk factors of gestational diabetes mellitus recurrence: a meta-analysis

The literature on risk factors for gestational diabetes mellitus recurrence is inconsistent and sometimes contradictory. The importance of inter-pregnancy interval and parity, remains unclear. We aimed to explore controversial risk factors for gestational diabetes mellitus recurrence, especially the modifiable ones, and to develop a prediction model in a cohort of women with gestational diabetes mellitus. A retrospective, population-based, cross-sectional cohort study was performed. The study included 788 women with gestational diabetes mellitus that delivered between 1991-2012 and had consecutive deliveries at a university affiliated hospital in Israel. Women with pre-existing diabetes were excluded. Factors associated with gestational diabetes mellitus recurrence were examined using log-binomial models to estimate prevalence ratios with 95 % confidence intervals. Multivariate analysis revealed that both inter-pregnancy interval and multiparity were significant risk factors for gestational diabetes mellitus recurrence. Other significant risk factors were maternal age, gestational diabetes mellitus diagnosis week, oral glucose tolerance test values, body mass index gain between pregnancies and insulin use; the latter and multiparity had the strongest effect size (PR ≥ 1.2). Among multiparous women, the association between inter-pregnancy interval and gestational diabetes mellitus recurrence was significantly lower (P = 0.0004) compared with primiparous women (PR = 1.11 [95 % CI 1.09-1.13] versus PR = 1.17 [95 % CI 1.15-1.20], respectively). The model we developed, predicts that reducing the inter-pregnancy interval and weight gain between pregnancies can reduce substantially the risk of gestational diabetes mellitus recurrence. The results suggest that weight gain and inter-pregnancy interval are modifiable risk factors for gestational diabetes mellitus recurrence. Our model could assist physicians in advising women with gestational diabetes mellitus in reducing the risk of recurrent gestational diabetes mellitus during subsequent pregnancies.

Modifiable risk factors for gestational diabetes recurrence

BACKGROUND: Early in the COVID-19 pandemic, it was noted that males seemed to have higher case-fatality rates than females. We examined the magnitude and consistency of the sex differences in age-specific case-fatality rates (CFRs) in seven countries. METHODS: Data on the cases and deaths from COVID-19, by sex and age group, were extracted from the national official agencies from Denmark, England, Israel, Italy, Spain, Canada and Mexico. Age-specific CFRs were computed for males and females separately. The ratio of the male to female CFRs were computed and meta-analytic methods were used to obtained pooled estimates of the male to female ratio of the CFRs over the seven countries, for all age-groups. Meta-regression and sensitivity analysis were conducted to evaluate the age and country contribution to differences. RESULTS: The CFRs were consistently higher in males at all ages. The pooled M:F CFR ratios were 1.71, 1.88, 2.11, 2.11, 1.84, 1.78 and 1.49, for ages 20-29, 30-39, 40-49, 50-59, 60-69, 70-79, 80+ respectively. In meta-regression, age group and country were associated with the heterogeneity in the CFR ratios. CONCLUSIONS: The sex differences in the age-specific CFRs are intriguing. Sex differences in the incidence and mortality have been found in many infectious diseases. For COVID-19, factors such as sex differences in the prevalence of underlying diseases may play a part in the CFR differences. However, the consistently greater case-fatality rates in males at all ages suggests that sex-related factors impact on the natural history of the disease. This could provide important clues as to the mechanisms underlying the severity of COVID-19 in some patients.

/pdf/sex-differences-in-the-case-fatality-rates-for-covid-19-a-1jtxeu8z6c.pdf

Naama Schwartz

Papers

The prevalence of gestational diabetes mellitus recurrence--effect of ethnicity and parity: a metaanalysis.

Decreased bone mineral density in young adult IgE-mediated cow's milk-allergic patients.

Risk factors of gestational diabetes mellitus recurrence: a meta-analysis

Modifiable risk factors for gestational diabetes recurrence

Sex differences in the case-fatality rates for COVID-19-A comparison of the age-related differences and consistency over seven countries.