Case Report: Everolimus reduced bone turnover markers but showed no clinical benefit in a patient with severe progressive osseous heteroplasia.

Background: Progressive osseous heteroplasia (POH) is an ultrarare genetic disorder characterized by an inactivating mutation in the GNAS gene that causes heterotopic ossification. Inhibition of the mammalian target of the rapamycin (mTOR) signalling pathway has been proposed as a therapy for progressive bone fibrodysplasia and non-genetic forms of bone heteroplasia. Herein, we describe the impact of using Everolimus as a rescue therapy for an identical twin girl exhibiting an aggressive clinical phenotype of POH. Methods: Clinical evaluation of the progression of the disease during Everolimus treatment was performed periodically. Cytokine markers involved in bone metabolism and protein markers related to bone activity were analyzed to explore bone turnover activity. Results: The patient received Everolimus therapy for 36 weeks. During treatment, no clinical improvement of the disease was perceived. Analysis of biochemical parameters, namely, ß-CTX (r 2 = -0.576, P-value = 0.016) and PNIP (r 2 = -0.598, P-value = 0.011), indicated that bone turnover activity was significantly reduced. Additionally, bone metabolism-related biomarkers showed only a significant positive correlation with PTH levels. Conclusions: Everolimus treatment did not modify the clinical progression of the disease in an aggressive form of POH, although an impact on the protein markers studied was observed.

Sex-biased expression of the TLR7 gene in severe COVID-19 patients: Insights from transcriptomics and epigenomics.

There is abundant epidemiological data indicating that the incidence of severe cases of coronavirus disease (COVID-19) is significantly higher in males than females worldwide. Moreover, genetic variation at the X-chromosome linked TLR7 gene has been associated with COVID-19 severity. It has been suggested that the sex-biased incidence of COVID-19 might be related to the fact that TLR7 escapes X-chromosome inactivation during early embryogenesis in females, thus encoding a doble dose of its gene product compared to males. We analyzed TLR7 expression in two acute phase cohorts of COVID-19 patients that used two different technological platforms, one of them in a multi-tissue context including saliva, nasal, and blood samples, and a third cohort that included different post-infection timepoints of long-COVID-19 patients. We additionally explored methylation patterns of TLR7 using epigenomic data from an independent cohort of COVID-19 patients stratified by severity and sex. In line with genome-wide association studies, we provide supportive evidence indicating that TLR7 has altered CpG methylation patterns and it is consistently downregulated in males compared to females in the most severe cases of COVID-19.

Routine infant vaccination of pneumococcal conjugate vaccines has decreased pneumonia across all age groups in Northern Spain.

Since the early 2000s, pneumococcal conjugate vaccines (PCVs) have been shown to be effective in the prevention of pneumonia and invasive pneumococcal diseases. In 2011, the Galician region incorporated PCV in the routine infant immunization, the very first stable program in Spain. We aim to assess direct and indirect benefits of PCV vaccination on all-cause pneumonia in the region across different age groups using an ecological study design. For this, we calculated the annual hospitalization rates using a hospital-based disease registry. We identified all-cause pneumonia, pneumococcal pneumonia and pneumococcal invasive diseases within the registry. Hospitalization rates were computed and compared across three study periods: pre-vaccination (1998-2003), early-vaccination (2005-2009) and routine-vaccination (2011-2015). Across Northern Spain, we identified 114,873 all-cause pneumonia hospitalizations, of which 24,808 were further diagnosed with pneumococcal pneumonia. The majority were elderly > 64 years (67.3%). Hospitalizations from all-cause pneumonia had a net increase from 20.6 (pre-PCV) and 21.4/10,000 (early) to 28.4/10,000 (routine) (+32.7%, p < .0001), this is attributed to the huge number of cases in the elderly age group. In contrast, a net reduction of incidence of hospitalized pneumococcal pneumonia was observed from 6.3/10,000 (pre-PCV) and 5.7/10,000 (early) to 2.4/10,000 (routine) cases (-57.9%, p < .0001). Thus, routine infant vaccination may have resulted to an overall decline of pneumococcal pneumonia in infants, as well as in elderly age groups. However, a paradoxical increase on all-cause pneumonia was observed in Galicia, mostly attributed to the growing number of cases in the elderly population.

Impact of rotavirus vaccination on childhood hospitalizations for seizures: Heterologous or unforeseen direct vaccine effects?

There is a growing interest in the possible relationship between rotavirus (RV) vaccine and hospitalizations due to childhood seizures. We explored variation in hospitalization rates after 9 years of vaccination against pre-vaccination period for children <5 years of age from Galicia (Northwest Spain) before and after the introduction of the RV vaccines. Hospitalization rates for childhood seizures in Galician children were compared before and after RV vaccine introduction (in 2007) using different statistical approaches, including time series analyses. Our study cohort totaled 7,712 children <5 years of age admitted to hospital between 2002 and 2015 for "all kind of childhood seizures". Hospitalization rates decreases steadily with reductions ranging from 22.3% (95% CI: 15.0-29.1) in 2008, to 50.9% (95% CI: 45.5-55.7) in 2014, and significant results were also observed for <1, 1, and 2-year-old children in comparison with pre-vaccination period hospitalization rate. Regression models indicate a negative association between RV vaccination and hospitalizations for all kind of seizures. In addition, time series analyses are consistent with this finding and predict that vaccination coverage will affect hospitalization rates for "all kind of seizures" after 9 months. The results strongly support that RV vaccination has significantly reduced hospitalization rates due to childhood seizures.

Biogeographical origin and timing of the founder ichthyosis TGM1 c.1187G > A mutation in an isolated Ecuadorian population.

An unusually high frequency of the lamellar ichthyosis TGM1 mutation, c.1187G > A, has been observed in the Ecuadorian province of Manabí. Recently, the same mutation has been detected in a Galician patient (Northwest of Spain). By analyzing patterns of genetic variation around this mutation in Ecuadorian patients and population matched controls, we were able to estimate the age of c.1187G > A and the time to their most recent common ancestor (TMRCA) of c.1187G > A Ecuadorian carriers. While the estimated mutation age is 41 generations ago (~1,025 years ago [ya]), the TMRCA of Ecuadorian c.1187G > A carrier haplotypes dates to just 17 generations (~425 ya). Probabilistic-based inferences of local ancestry allowed us to infer a most likely European origin of a few (16% to 30%) Ecuadorian haplotypes carrying this mutation. In addition, inferences on demographic historical changes based on c.1187G > A Ecuadorian carrier haplotypes estimated an exponential population growth starting ~20 generations, compatible with a recent founder effect occurring in Manabí. Two main hypotheses can be considered for the origin of c.1187G > A: (i) the mutation could have arisen in Spain >1,000 ya (being Galicia the possible homeland) and then carried to Ecuador by Spaniards in colonial times ~400 ya, and (ii) two independent mutational events originated this mutation in Ecuador and Galicia. The geographic and cultural characteristics of Manabí could have favored a founder effect that explains the high prevalence of TGM1 c.1187G > A in this region.

A 2-transcript host cell signature distinguishes viral from bacterial diarrhea and it is influenced by the severity of symptoms.

Recently, a biomarker signature consisting of 2-transcript host RNAs was proposed for discriminating bacterial from viral infections in febrile children. We evaluated the performance of this signature in a different disease scenario, namely a cohort of Mexican children (n = 174) suffering from acute diarrhea of different infectious etiologies. We first examined the admixed background of the patients, indicating that most of them have a predominantly Native American genetic ancestry with a variable amount of European background (ranging from 0% to 57%). The results confirm that the RNA test can discriminate between viral and bacterial causes of infection (t-test; P-value = 6.94×10-11; AUC = 80%; sensitivity: 68% [95% CI: 55%-79%]; specificity: 84% [95% CI: 78%-90%]), but the strength of the signal differs substantially depending on the causal pathogen, with the stronger signal being that of Shigella (P-value = 3.14 × 10-12; AUC = 89; sensitivity: 70% [95% CI: 57%-83%]; specificity: 100% [95% CI: 100%-100%]). The accuracy of this test improves significantly when excluding mild cases (P-value = 2.13 × 10-6; AUC = 85%; sensitivity: 79% [95% CI: 58%-95%]; specificity: 78% [95% CI: 65%-88%]). The results broaden the scope of previous studies by incorporating different pathogens, variable levels of disease severity, and different ancestral background of patients, and add confirmatory support to the clinical utility of these 2-transcript biomarkers.

The geographic mosaic of Ecuadorian Y-chromosome ancestry.

Ecuadorians originated from a complex mixture of Native American indigenous people with Europeans and Africans. We analyzed Y-chromosome STRs (Y-STRs) in a sample of 415 Ecuadorians (145 using the AmpFlSTR® Yfiler™ system [Life Technologies, USA] and 270 using the PowerPlex®Y23 system [Promega Corp., USA]; hereafter Yfiler and PPY23, respectively) representing three main ecological continental regions of the country, namely Amazon rainforest, Andes, and Pacific coast. Diversity values are high in the three regions, and the PPY23 exhibits higher discrimination power than the Yfiler set. While summary statistics, AMOVA, and RST distances show low to moderate levels of population stratification, inferred ancestry derived from Y-STRs reveal clear patterns of geographic variation. The major ancestry in Ecuadorian males is European (61%), followed by an important Native American component (34%); whereas the African ancestry (5%) is mainly concentrated in the Northwest corner of the country. We conclude that classical procedures for measuring population stratification do not have the desirable sensitivity. Statistical inference of ancestry from Y-STRS is a satisfactory alternative for revealing patterns of spatial variation that would pass unnoticed when using popular statistical summary indices.

Phylogeographic and genome-wide investigations of Vietnam ethnic groups reveal signatures of complex historical demographic movements.

The territory of present-day Vietnam was the cradle of one of the world's earliest civilizations, and one of the first world regions to develop agriculture. We analyzed the mitochondrial DNA (mtDNA) complete control region of six ethnic groups and the mitogenomes from Vietnamese in The 1000 Genomes Project (1000G). Genome-wide data from 1000G (~55k SNPs) were also investigated to explore different demographic scenarios. All Vietnamese carry South East Asian (SEA) haplotypes, which show a moderate geographic and ethnic stratification, with the Mong constituting the most distinctive group. Two new mtDNA clades (M7b1a1f1 and F1f1) point to historical gene flow between the Vietnamese and other neighboring countries. Bayesian-based inferences indicate a time-deep and continuous population growth of Vietnamese, although with some exceptions. The dramatic population decrease experienced by the Cham 700 years ago (ya) fits well with the Nam tien ("southern expansion") southwards from their original heartland in the Red River Delta. Autosomal SNPs consistently point to important historical gene flow within mainland SEA, and add support to a main admixture event occurring between Chinese and a southern Asian ancestral composite (mainly represented by the Malay). This admixture event occurred ~800 ya, again coinciding with the Nam tien.

Salivary epidermal growth factor correlates with hospitalization length in rotavirus infection.

BACKGROUND: The IFI27 interferon gene expression has been found to be largely increased in rotavirus (RV)-infected patients. IFI27 gene encodes for a protein of unknown function, very recently linked to epidermal proliferation and related to the epidermal growth factor (EGF) protein. The EGF is a low-molecular-weight polypeptide that is mainly produced by submandibular and parotid glands, and it plays an important physiological role in the maintenance of oro-esophageal and gastric tissue integrity. Our aim was to determine salivary EGF levels in RV-infected patients in order to establish its potential relationship with IFI27 increased expression and EGF-mediated mucosal protection in RV infection. METHODS: We conducted a prospective comparative study using saliva samples from 27 infants infected with RV (sampled at recruitment during hospital admission and at convalescence, i.e. at least 3 months after recovery) and from 36 healthy control children. RESULTS: Median (SD) EGF salivary concentration was 777 (529) pg/ml in RV-infected group at acute phase and 356 (242) pg/m at convalescence, while it was 337 (119) pg/ml in the healthy control group. A significant association was found between EGF levels and hospitalization length of stay (P-value = 0.022; r2 = -0.63). CONCLUSIONS: The salivary levels of EGF are significantly increased during the acute phase of natural RV infection, and relate to length of hospitalization. Further assessment of this non-invasive biomarker in RV disease is warranted.

Incidence and risk factor prevalence of community-acquired pneumonia in adults in primary care in Spain (NEUMO-ES-RISK project).

BACKGROUND: Community-acquired pneumonia (CAP) is a major cause of morbidity and mortality in adults even in developed countries. Several lifestyle factors and comorbidities have been linked to an increased risk, although their prevalence has not been well documented in the primary care setting. The aim of this study is to assess the incidence, risk factor and comorbid conditions distribution of CAP in adults in primary care in Spain. METHODS: Retrospective observational study in adults (>18 years-old) with CAP diagnosed and attended at primary care in Spain between 2009 and 2013, using the Computerized Database for Pharmacoepidemiological Studies in Primary Care (BIFAP). RESULTS: Twenty-eight thousand four hundred thirteen patient records were retrieved and analyzed. Mean age (standard deviation): 60.5 (20.3) years, 51.7 % males. Global incidence of CAP in adults was estimated at 4.63 per 1000 persons/year. CAP incidence increased progressively with age, ranging from a 1.98 at 18-20 years of age to 23.74 in patients over 90 years of age. According to sex, global CAP incidence was slightly higher in males (5.04) than females (4.26); CAP incidence from 18 to 65 year-olds up was comparable between males (range: 2.18-5.75) and females (range: 1.47-5.21), whereas from 65 years of age, CAP incidence was noticeable higher in males (range: 7.06-36.93) than in females (range: 5.43-19.62). Average prevalence of risk factors was 71.3 %, which increased with age, doubling the risk in males by the age of 75 (females 20 % vs males 40 %). From 55 years of age, at least one risk factor was identified in 85.7 % of cases: one risk factor (23.8 %), two risk factors (23.4 %), three or more risk factors (38.5 %). Major risk factors were: metabolic disease (27.4 %), cardiovascular disease (17.8 %) and diabetes (15.5 %). CONCLUSIONS: The annual incidence of CAP in primary care adults in Spain is high, comparable between males and females up to 65 years of age, but clearly increasing in males from that age. CAP risk increases with age and doubles in males older than 75 years. The majority of CAP cases in patients over 55 years of age is associated to at least one risk factor. The main risk factors associated were metabolic disease, cardiovascular disease, and diabetes.