Immunological profile in a family with nephrogenic diabetes insipidus with a novel 11 kb deletion in AVPR2 and ARHGAP4 genes

Background  

Congenital nephrogenic diabetes insipidus (NDI) is characterised by an inability to concentrate urine despite normal or elevated plasma levels of the antidiuretic hormone arginine vasopressin. We report a Japanese extended family with NDI caused by an 11.2-kb deletion that includes the entire AVPR2 locus and approximately half of the Rho GTPase-activating protein 4 (ARHGAP4) locus. ARHGAP4 belongs to the RhoGAP family, Rho GTPases are critical regulators of many cellular activities, such as motility and proliferation which enhances intrinsic GTPase activity.     

Loss-of-function variants in SEMA3F and PLXNA3 encoding semaphorin-3F and its receptor plexin-A3 respectively cause idiopathic hypogonadotropic hypogonadism

PurposeIdiopathic hypogonadotropic hypogonadism (IHH) is characterized by absent puberty and subsequent infertility due to gonadotropin-releasing hormone (GnRH) deficiency. IHH can be accompanied by normal or compromised olfaction (Kallmann syndrome). Several semaphorins are known potent modulators of GnRH, olfactory, and vomeronasal system development. In this study, we investigated the role of Semaphorin-3F signaling in the etiology of IHH.MethodsWe screened 216 IHH patients by exome sequencing. We transiently transfected HEK293T cells with plasmids encoding wild type (WT) or corresponding variants to investigate the functional consequences. We performed fluorescent IHC to assess SEMA3F and PLXNA3 expression both in the nasal region and at the nasal/forebrain junction during the early human fetal development.ResultsWe identified ten rare missense variants in SEMA3F and PLXNA3 in 15 patients from 11 independent families. Most of these variants were predicted to be deleterious by functional assays. SEMA3F and PLXNA3 are both expressed along the olfactory nerve and intracranial projection of the vomeronasal nerve/terminal nerve. PLXNA1-A3 are expressed in the early migratory GnRH neurons.ConclusionSEMA3F signaling through PLXNA1-A3 is involved in the guidance of GnRH neurons and of olfactory and vomeronasal nerve fibers in humans. Overall, our findings suggest that Semaphorin-3F signaling insufficiency contributes to the pathogenesis of IHH.     

Rare variants in KDR,encoding VEGF Receptor 2, are associated with tetralogy of Fallot

PurposeRare genetic variants in KDR, encoding the vascular endothelial growth factor receptor 2 (VEGFR2), have been reported in patients with tetralogy of Fallot (TOF). However, their role in disease causality and pathogenesis remains unclear.MethodsWe conducted exome sequencing in a familial case of TOF and large-scale genetic studies, including burden testing, in >1,500 patients with TOF. We studied gene-targeted mice and conducted cell-based assays to explore the role of KDR genetic variation in the etiology of TOF.ResultsExome sequencing in a family with two siblings affected by TOF revealed biallelic missense variants in KDR. Studies in knock-in mice and in HEK 293T cells identified embryonic lethality for one variant when occurring in the homozygous state, and a significantly reduced VEGFR2 phosphorylation for both variants. Rare variant burden analysis conducted in a set of 1,569 patients of European descent with TOF identified a 46-fold enrichment of protein-truncating variants (PTVs) in TOF cases compared to controls (P = 7 × 10^-11).ConclusionRare KDR variants, in particular PTVs, strongly associate with TOF, likely in the setting of different inheritance patterns. Supported by genetic and in vivo and in vitro functional analysis, we propose loss-of-function of VEGFR2 as one of the mechanisms involved in the pathogenesis of TOF.     

DLG2 variants in patients with pubertal disorders

PurposeImpaired function of gonadotropin-releasing hormone (GnRH) neurons can cause a phenotypic spectrum ranging from delayed puberty to isolated hypogonadotropic hypogonadism (IHH). We sought to identify a new genetic etiology for these conditions.MethodsExome sequencing was performed in an extended family with autosomal dominant, markedly delayed puberty. The effects of the variant were studied in a GnRH neuronal cell line. Variants in the same gene were sought in a large cohort of individuals with IHH.ResultsWe identified a rare missense variant (F900V) in DLG2 (which encodes PSD-93) that cosegregated with the delayed puberty. The variant decreased GnRH expression in vitro. PSD-93 is an anchoring protein of NMDA receptors, a type of glutamate receptor that has been implicated in the control of puberty in laboratory animals. The F900V variant impaired the interaction between PSD-93 and a known binding partner, Fyn, which phosphorylates NMDA receptors. Variants in DLG2 that also decreased GnRH expression were identified in three unrelated families with IHH.ConclusionThe findings indicate that variants in DLG2/PSD-93 cause autosomal dominant delayed puberty and may also contribute to IHH. The findings also suggest that the pathogenesis involves impaired NMDA receptor signaling and consequently decreased GnRH secretion.     

OXGR1 is a candidate disease gene for human calcium oxalate nephrolithiasis

PurposeNephrolithiasis (NL) affects 1 in 11 individuals worldwide, leading to significant patient morbidity. NL is associated with nephrocalcinosis (NC), a risk factor for chronic kidney disease. Causative genetic variants are detected in 11% to 28% of NL and/or NC, suggesting that additional NL/NC-associated genetic loci await discovery. Therefore, we employed genomic approaches to discover novel genetic forms of NL/NC.MethodsExome sequencing and directed sequencing of the OXGR1 locus were performed in a worldwide NL/NC cohort. Putatively deleterious, rare OXGR1 variants were functionally characterized.ResultsExome sequencing revealed a heterozygous OXGR1 missense variant (c.371T>G, p.L124R) cosegregating with calcium oxalate NL and/or NC disease in an autosomal dominant inheritance pattern within a multigenerational family with 5 affected individuals. OXGR1 encodes 2-oxoglutarate (α-ketoglutarate [AKG]) receptor 1 in the distal nephron. In response to its ligand AKG, OXGR1 stimulates the chloride-bicarbonate exchanger, pendrin, which also regulates transepithelial calcium transport in cortical connecting tubules. Strong amino acid conservation in orthologs and paralogs, severe in silico prediction scores, and extreme rarity in exome population databases suggested that the variant was deleterious. Interrogation of the OXGR1 locus in 1107 additional NL/NC families identified 5 additional deleterious dominant variants in 5 families with calcium oxalate NL/NC. Rare, potentially deleterious OXGR1 variants were enriched in patients with NL/NC compared with Exome Aggregation Consortium controls (χ² = 7.117, P = .0076). Wild-type OXGR1-expressing Xenopus oocytes exhibited AKG-responsive Ca²⁺ uptake. Of 5 NL/NC-associated missense variants, 5 revealed impaired AKG-dependent Ca²⁺ uptake, demonstrating loss of function.ConclusionRare, dominant loss-of-function OXGR1 variants are associated with recurrent calcium oxalate NL/NC disease.     

Shiga toxin-producing Escherichia coli: incidence and clinical features in a setting with complete screening of patients with suspected infective diarrhoea

ObjectivesShiga toxin-producing Escherichia coli (STEC) causes diarrhoeal disease, bloody diarrhoea, and haemolytic uraemic syndrome. The aim of this study was to describe the incidence of STEC and the clinical features of STEC patients from a well-defined Danish population in which all fecal samples of patients with suspected infective gastroenteritis were analysed for STEC.MethodsIn this population-based cohort study, all stool samples referred to two clinical microbiology laboratories were screened for STEC by culture and/or PCR. Epidemiological (n=170) and clinical (n=209) characteristics were analysed using data from local and national registries.ResultsOverall, 75,132 samples from 30,073 patients were screened resulting in 217 unique STEC-isolates. The epidemiological analysis showed an incidence of 10.1 cases per 100,000 person-years, which was more than twofold higher than the incidence in the rest of Denmark (3.4 cases per 100,000 person-years, p <0.001). Three groups were associated with a higher incidence: age <5 years (n=28, p <0.001), age ≥65 years (n=38, p 0.045), and foreign ethnicity (n=27, p 0.003). In the clinical analysis, patients with STEC harbouring only the Shiga toxin 1 gene (stx₁-only isolates) showed a lower frequency of acute (n=11, p <0.05) and bloody diarrhoea (n=5, p <0.05) and a higher frequency of gastrointestinal symptoms for ≥3 months (n=8, p <0.05) than the other STEC patients.ConclusionsWe report a more than twofold higher incidence in the project area compared with the rest of Denmark, indicating that patients remain undiagnosed when selective STEC screening is used. We found an association between patients with stx₁-only isolates and long-term gastrointestinal symptoms.     

Correlation of antifungal susceptibility and sequence types within Cryptococcus neoformans VNI from HIV patients,and ERG11 gene polymorphism

IntroductionHere we tested the correlation between minimum inhibitory concentrations (MICs) of major antifungal agents and sequence types (STs) within Cryptococcus neoformans VNI isolates, and explored the ERG11 gene of included strains.Materials and methodsWe analysed 23 C. neoformans strains categorised into two groups according to the distribution of the ST profile in Kinshasa clinics (Democratic Republic of Congo): major ST [ST93 (n = 15)], and less common STs [ST659 (n = 2), ST5 (n = 2), ST4 (n = 1), ST 53 (n = 1), ST31 (n = 1), and ST69 (n = 1)]. The MICs of the major antifungal agents [amphotericin B (AMB), 5-fluorocytosine (5FC) and fluconazole (FCZ)] were determined following EUCAST guidelines. ERG11 gene sequences were extracted from whole genome sequence of the isolates and compared with the wild-type gene sequence of the C. neoformans VNI.ResultsAlthough major ST isolates appeared to have lower median MICs for AMB and 5FU than less common ST isolates (0.50 vs. 0.75 mg/L for AMB, 2 vs. 4 mg/L for 5FU, respectively), FCZ susceptibility was similar in both groups (4 mg/L) (p-value >0.05). The susceptibility profile of C. neoformans strains separately considered did not significantly affect the patients’ clinical outcomes (p-value >0.05). Furthermore, two structural modalities of the ERG11 gene were observed: (1) that of the reference gene, and (2) that containing two exonic silent point substitutions, and one intronic point substitution located in a sequence potentially involved in pre-mRNA splicing (c.337-22C > T); with no association with the MICs of the isolates (p-value >0.05).ConclusionsThe lack of association/correlation found in this study calls for further investigations to better understand the mechanisms of C. neoformans resistance to antifungal agents.     

GENEDIA Multi Influenza Ag Rapid Test for detection and H1, H3, and H5 subtyping of influenza viruses

BackgroundRapid identification and subtype determination of influenza virus is important in managing infected patients. Rapid influenza diagnostic tests (RIDTs) are widely used in this manner, but most can only detect influenza A and B viruses without subtyping. A new RIDT, GENEDIA Multi Influenza Ag Rapid Test (GENEDIA), was developed for detection of influenza A and B viruses and also subtyping of influenza A to H1, H3, H5 which has not been possible with other RIDTs.ObjectivesAssess the performance of GENEDIA.Study designNasopharyngeal swabs were collected from 274 clinically suspected patients (influenza A/H1N1/2009 (n = 50), influenza A/H3 (n = 50), influenza B (n = 73) and influenza-negative (n = 101)) and analyzed with the real-time RT-PCR, GENEDIA, SD Bioline Influenza Ag, and Alere BinaxNow Influenza A&B Card. Also, 46 fecal specimens (H5N2 (n = 3), H5N3 (n = 3)) of spot-billed duck were analyzed with RT-PCR and GENEDIA.ResultsCompared to real-time RT-PCR, the sensitivities of GENEDIA, SD Bioline Influenza Ag, and Alere BinaxNow Influenza A&B Card were 73.0%, 57.0%, 58.0% for influenza A, respectively, and 68.5%, 65.8%, 57.5% for influenza B, respectively. Specifically, the sensitivity of GENEDIA was 70.0% for influenza A/H1N1/2009 and 76.0% for influenza A/H3. From the avian influenza samples, GENEDIA detected all six H5 subtype without any cross-reactions.ConclusionThe GENEDIA Multi Influenza Ag Rapid Test was sensitive in detecting influenza viruses compared with other commercial RIDTs and also useful for rapid subtype determination of influenza A.     

Impact of rare variants in ARHGAP29 to the etiology of oral clefts: role of loss‐of‐function vs missense variants

Non‐syndromic cleft lip with or without cleft palate (NSCL/P) is a prevalent, complex congenital malformation. Genome‐wide association studies (GWAS) on NSCL/P have consistently identified association for the 1p22 region, in which ARHGAP29 has emerged as the main candidate gene. ARHGAP29 re‐sequencing studies in NSCL/P patients have identified rare variants; however, their clinical impact is still unclear. In this study we identified 10 rare variants in ARHGAP29, including five missense, one in‐frame deletion, and four loss‐of‐function (LoF) variants, in a cohort of 188 familial NSCL/P cases. A significant mutational burden was found for LoF (Sequence Kernel Association Test, p = 0.0005) but not for missense variants in ARHGAP29, suggesting that only LoF variants contribute to the etiology of NSCL/P. Penetrance was estimated as 59%, indicating that heterozygous LoF variants in ARHGAP29 confer a moderate risk to NSCL/P. The GWAS hits in IRF6 (rs642961) and 1p22 (rs560426 and rs4147811) do not seem to contribute to the penetrance of the phenotype, based on co‐segregation analysis. Our data show that rare variants leading to haploinsufficiency of ARHGAP29 represent an important etiological clefting mechanism, and genetic testing for this gene might be taken into consideration in genetic counseling of familial cases.     

Low frequency of Fabry disease in patients with common heart disease

PurposeTo test the hypothesis that undiagnosed patients with Fabry disease exist among patients affected by common heart disease.MethodsGlobotriaosylceramide in random whole urine using tandem mass spectroscopy, α-galactosidase A activity in dried blood spots, and next-generation sequencing of pooled or individual genomic DNA samples supplemented by Sanger sequencing.ResultsWe tested 2,256 consecutive patients: 852 women (median age 65 years (19–95)) and 1,404 men (median age 65 years (21–92)). The primary diagnoses were coronary artery disease (n = 994), arrhythmia (n = 607), cardiomyopathy (n = 138), and valvular disease (n = 568). Urinary globotriaosylceramide was elevated in 15% of patients and 15 males had low α-galactosidase A activity. GLA variants found included R118C (n = 2), D83N, and D313Y (n = 7); IVS6-22 C>T, IVS4-16 A>G, IVS2+990C>A, 5′UTR-10 C>T (n = 4), IVS1-581 C>T, IVS1-1238 G>A, 5′UTR-30 G>A, IVS2+590C>T, IVS0-12 G>A, IVS4+68A>G, IVS0-10 C>T, IVS2-81–77delCAGCC, IVS2-77delC. Although the pathogenicity of several of these missense mutations and complex intronic haplotypes has been controversial, none of the patients screened in this study were diagnosed definitively with Fabry disease.ConclusionThis population of patients with common heart disease did not contain a substantial number of patients with undiagnosed Fabry disease. GLA gene sequencing is superior to urinary globotriaosylceramide or α-galactosidase A activity in the screening for Fabry disease.     

In vitro activity of olorofim against Aspergillus fumigatus sensu lato clinical isolates: activity is retained against isolates showing resistance to azoles and/or amphotericin B

ObjectivesNew antifungal drugs, such as olorofim, may overcome the problem of resistance in Aspergillus fumigatus. We here report the activity of olorofim against a set of A. fumigatus sensu lato recently collected in Spain.MethodsA total of 332 A. fumigatus sensu lato clinical isolates collected in a multicentre study conducted in Spain in 2019 and comprising susceptible and resistant isolates to azoles and/or amphotericin B were tested. Isolates distributed among the following species: A. fumigatus sensu stricto (n = 312), Aspergillus lentulus (n = 6), Aspergillus fumigatiaffinis (n = 5), Neosartorya tsurutae (n = 3), Neosartorya udagawae (n = 3), Aspergillus novofumigatus (n = 2), and Aspergillus thermomutatus (n = 1). Azole resistance was found in 44 A. fumigatus sensu stricto isolates that harboured the following cyp51A gene substitutions: TR₃₄-L98H (n = 24), G54 (n = 5), TR₄₆/Y121F/T289A (n = 1), other mutations (n = 4), and gene wild type (n = 10). Isolates were tested for antifungal susceptibility to olorofim using European Committee on Antimicrobial Susceptibility Testing (EUCAST) E.Def. 9.4 methodology.ResultsOlorofim minimum inhibitory concentrations against A. fumigatus sensu stricto isolates ranged from 0.008 to 0.125 mg/L and in vitro activity of the drug was not impacted by the presence of azole/amphotericin B resistance. Azole resistance and amphotericin B resistance was found in 18 and 13 cryptic species isolates, respectively. Olorofim showed high in vitro activity against cryptic species isolates and minimum inhibitory concentrations ranged from 0.004 to 0.016 mg/L, regardless of the presence of resistance to other drugs.DiscussionOlorofim showed in vitro activity against both A. fumigatus sensu stricto and cryptic species clinical isolates and was active against isolates showing resistance to azoles and/or amphotericin B.     

Tocilizumab versus baricitinib in hospitalized patients with severe COVID-19: an open label,randomized controlled trial

ObjectiveRandomized controlled trials comparing tocilizumab and baricitinib in patients with coronavirus disease 2019 (COVID-19) are needed. This was an open-label, randomized controlled trial aiming to address this unmet need.MethodsTo determine whether baricitinib was non-inferior to tocilizumab, we assessed whether the upper boundary of the two-sided 95% CI of the hazard ratio (HR) did not exceed 1.50. The primary outcome was mechanical ventilation or death by day 28. Secondary outcomes included time to hospital discharge by day 28 and change in WHO progression scale at day 10.ResultsWe assigned 251 patients with COVID-19 and a PaO_2/FiO₂ ratio of <200 to receive either tocilizumab (n = 126) or baricitinib (n = 125) plus standard of care. Baricitinib was non-inferior to tocilizumab for the primary composite outcome of mechanical ventilation or death by day 28 (mechanical ventilation or death for patients who received baricitinib, 39.2% [n = 49/125]; mechanical ventilation or death for patients who received tocilizumab, 44.4% [n = 56/126]; HR, 0.83; 95% CI, 0.56–1.21; p 0.001 for non-inferiority). Baricitinib was non-inferior to tocilizumab for the time to hospital discharge within 28 days (patients who received baricitinib- discharged alive: 58.4% [n = 73/125] vs. patients who received tocilizumab- discharged alive: 52.4% [n = 66/126]; HR, 0.85; 95% CI, 0.61–1.18; p < 0.001 for non-inferiority). There was no significant difference between the baricitinib and tocilizumab arms in the change in WHO scale at day 10 (0.0 [95% CI, 0.0–0.0] vs. 0.0 [95% CI, 0.0–1.0]; p 0.83).DiscussionIn the setting of this trial, baricitinib was non-inferior to tocilizumab with regards to the composite outcome of mechanical ventilation or death by day 28 and the time to discharge by day 28 in patients with severe COVID-19.     

Immune checkpoint inhibitor-induced myositis,the earliest and most lethal complication among rheumatic and musculoskeletal toxicities

BackgroundIn addition to restoring anti-tumor immune responses, immune checkpoint inhibitors (ICI) may also induce immune-related adverse events (irAE) that can affect any organ. We aim to determine the spectrum, timing, clinical features, and fatalities of rheumatic and musculoskeletal immune-related adverse events (RMS-irAE) associated with ICI.Patients MethodsWe performed an observational, retrospective, pharmacovigilance study using the World Health Organization international pharmacovigilance database, VigiBase, from inception to January 2019. RMS-irAE reporting rate on ICI versus full database was performed using disproportionality analysis with computation of reporting-odds-ratios (ROR) and a Bayesian disproportional estimate (information component, IC). IC₀₂₅ (lower end of the IC 95% credibility interval) >0 is deemed significant.ResultsWe identified 1288 RMS-irAE significantly associated with ICI: polymyalgia rheumatica (n = 76, ROR = 14.6 [11.6–18.4], IC₀₂₅ = 3.34), sarcoidosis (n = 94; ROR = 9.6 [7.9–11.9]; IC₀₂₅ = 2.85), Sjogren's syndrome (n = 49; ROR = 6.9 [5.2–9.2]; IC₀₂₅ = 2.24), myositis (n = 465; ROR = 4.9 [4.5–5.4]; IC₀₂₅ = 2.12), arthritis (n = 606; ROR = 1.4 [1.3–1.5]; IC₀₂₅ = 0.34) and scleroderma (n = 17; ROR = 2.0 [1.2–3.2]; IC₀₂₅ = 0.17). Arthritis, myositis, and Sjogren's syndrome were over-reported in patients treated with ICI combination versus those treated with ICI monotherapy (ROR = 1.6–2.9, p < .05) and more frequently reported on anti-PD1/PDL1 monotherapy vs. anti-CTLA4 monotherapy (2.1–4.4, p < .05). Median time to onset occurred early for myositis (31 days [19.2–57.8]) and was the most delayed for scleroderma (395 days [323.8–457.2], p < .0001). The fatality rate for RMS-irAE ranged from 24% for myositis (n = 106/441) (up to 56.7% with concurrent myocarditis) to [0–6.7%] for other RMS-irAE (p < .0001).ConclusionsClinicians should be aware of the spectrum of RMS-irAE. Myositis can be particularly life-threatening, particularly when associated with myocarditis.     

Fluconazole-resistant Candida parapsilosis clonally related genotypes: first report proving the presence of endemic isolates harbouring the Y132F ERG11 gene substitution in Spain

ObjectivesWe report here for the first time the presence of Candida parapsilosis isolates harbouring the Y132F ERG11 gene substitution in patients admitted to a Spanish hospital.MethodsWe studied the available (n = 104) C parapsilosis isolates from patients admitted to the Son Espases reference hospital in the Balearic Islands from 1 April 2019 to 30 November 2020. Isolates were sourced from 70 patients: catheter (n = 41), blood cultures (n = 37), lower respiratory tract (n = 15), intra-abdominal (n = 8), and other samples (n = 3). Isolates were genotyped and tested for antifungal susceptibilities to amphotericin B, triazoles, anidulafungin, and micafungin using EUCAST E.Def 7.3.2. The ERG11 gene was sequenced in fluconazole-resistant isolates.ResultsAmong the 104 isolates, fluconazole and voriconazole resistance was found in 87 (84%) and 30 (29%) isolates, respectively; all isolates were fully susceptible to echinocandins and amphotericin B. All fluconazole-resistant isolates harboured the Y132F substitution in the ERG11 gene and were grouped into 11 clonally related genotypes. A genotype accounted for 70% (61/87) of fluconazole-resistant isolates. Genotypes involving the fluconazole-resistant isolates were different from those found in the remaining fluconazole-susceptible genotypes. Fifty-six patients harboured fluconazole-resistant genotypes, and 35 of the 56 had candidaemia (48%), abdominal candidiasis (17%), or other forms of candidiasis (35%). Only 20% of the study patients infected by fluconazole-resistant genotypes had a history of azole use.DiscussionFluconazole resistance in C parapsilosis isolates from patients admitted to this reference hospital is not attributable to prior azole use, but rather to the presence of a group of fluconazole-resistant C parapsilosis genotypes that have become endemic.     

Infectious meningitis and encephalitis in adults in Denmark: a prospective nationwide observational cohort study (DASGIB)

ObjectivesTo monitor epidemiological trends of infectious meningitis (bacterial and viral) and encephalitis in Denmark.MethodsNationwide prospective observational study of all cases of proven community-acquired infectious meningitis and encephalitis in adults treated in all infectious diseases departments in Denmark from 1 January 2015 to 30 June 2016. We included data on symptoms, aetiology, treatment and outcome assessed by the Glasgow Outcome Scale (GOS) 30 days after discharge. GOS 1–4 was categorized as unfavourable outcome.ResultsDuring 18 months of observation, we identified 252 cases of viral meningitis (3.6/100 000/year), 214 cases of bacterial meningitis (3.1/100 000/year) and 96 cases of infectious encephalitis (1.4/100 000/year). In bacterial meningitis, Streptococcus pneumoniae was the most frequent infectious agent (n = 101) followed by Staphylococcus aureus (n = 24) and β-haemolytic streptococci (n = 14). Meningococcal meningitis was rare (n = 11). In encephalitis, herpes simplex virus type 1 was most common (n = 37) followed by varicella zoster virus (n = 20), whereas varicella zoster virus (n = 61) was most common in viral meningitis followed by enterovirus (n = 50) and herpes simplex virus type 2 (n = 46). Case fatality and unfavourable outcome occurred in 31/214 (15%) and 96/214 (45%) with bacterial meningitis and in 5/96 (5%) and 55/89 (62%) with encephalitis. For viral meningitis, unfavourable outcome occurred in 41/252 (17%).ConclusionsThe epidemiology and clinical presentation of the examined central nervous system infections differed considerably and bacterial meningitis was more frequent than previously estimated. Overall prognosis remains poor for bacterial meningitis and encephalitis. Prospective nationwide clinical databases of central nervous system infections may be superior to epidemiological monitoring based on notifications or laboratory systems.     

Tumor detection rates in screening of individuals with SDHx-related hereditary paraganglioma–pheochromocytoma syndrome

PurposeMinimal data exist regarding the efficacy of screening protocols for individuals with SDHx germline pathogenic variants with hereditary paraganglioma–pheochromocytoma syndrome. This study aimed to evaluate the SDHx-related tumor detection rate in individuals undergoing clinical screening protocols.MethodsA multicenter retrospective longitudinal observational study was conducted. Individuals with germline SDHx pathogenic variants underwent clinical whole-body imaging and biochemical testing.ResultsTwo hundred sixty-three individuals with SDHx germline pathogenic variants completed 491 imaging screens. Individuals with SDHB germline pathogenic variants were most common (n = 188/263, 72%), followed by SDHD (n = 35/263, 13%) and SDHC (n = 28/263, 11%). SDHx-related tumors were found in 17% (n = 45/263) of the cohort. Most SDHx-related tumors were identified on baseline imaging screen (n = 39/46, 85%). Individuals with SDHD pathogenic variants had the highest tumor detection rate (n = 14/35, 40%). Of imaging screens identifying SDHx-related paraganglioma/pheochromocytoma, 29% (n = 12/41) had negative biochemical testing. Secondary actionable findings were identified in 15% (n = 75/491) of imaging screens.ConclusionCurrent SDHx screening protocols are effective at identifying SDHx-related tumors. Tumor detection rates vary by SDHx gene and screening has the potential to uncover actionable secondary findings. Imaging is an essential part of the screening process as biochemical testing alone does not detect all disease.     

Effects of flaxseed on blood pressure,body mass index,and total cholesterol in hypertensive patients: A randomized clinical trial

ObjectivesGiven the antioxidant properties of flaxseed and its biologically active ingredients, this study was conducted to determine the effects of flaxseed supplementation on body mass index (BMI), blood pressure, and total cholesterol levels in patients with hypertension.MethodsIn this triple-blind clinical trial, 112 patients, with an age range of 35 to 70 years, were randomized to 2 groups receiving 10 g (n = 45) and 30 g (n = 45) of flaxseed supplementation and 1 group receiving placebo (n = 45) for 12 weeks by stratified block randomization. They were evaluated in terms of systolic (SBP) and diastolic blood pressure (DBP), BMI, and total serum cholesterol. Physical activity was measured using the International Physical Activity Questionnaire–Short Form (IPAQ–SF) and food intake was assessed using the Food Frequency Questionnaire (FFQ). The data were analyzed with SPSS, version 22, using the chi-square, Kruskal–Wallis, repeated measures analysis, ANOVA, and ANCOVA tests.ResultsThe interaction effects among the study groups and time on the mean SBP (p = 0.001), DBP (p = 0.001), total cholesterol level (p = 0.032), and BMI (p < 0.001) were significant. During the study, the 30-g group achieved the best results, so that a 13.38-unit decrease in SBP was observed compared to a 1.72 unit increase in the placebo group and a 5.6-unit decrease in DBP was measured compared to a 2.39 unit increase in the placebo group. BMI decreased by 0.86 units compared to 0.06 units in the placebo group. Total cholesterol also decreased by 20.4 units compared to 11.86 units in the placebo group.ConclusionThe results of this study showed that flaxseed can be effective in reducing blood pressure, total cholesterol, and body mass index in hypertensive patients in a twelve-week period.     

Histopathological features of systemic sclerosis-associated myopathy: A scoping review

BackgroundScleromyositis (SM) is an emerging subset of myositis associated with features of systemic sclerosis (SSc) but it is currently not recognized as a distinct histopathological subset by the European NeuroMuscular Center (ENMC). Our aim was to review studies reporting muscle biopsies from SSc patients with myositis and to identify unique histopathological features of SM.MethodsA scoping review was conducted and included all studies reporting histopathological findings in SSc patients with myositis searching the following databases: PubMed, MEDLINE, EMBASE, CINAHL and EBM-Reviews. Clinical, serological, and histopathological data were extracted using a standardized protocol.ResultsOut of 371 citations, 77 studies that included 559 muscle biopsies were extracted. Fifty-seven percent (n = 227/400) had inflammatory infiltrates, predominantly T cells, which were endomysial (49%), perimysial (42%) and perivascular (41%). Few studies (18%, n = 8/44) evaluated the presence of B-cells. Myofiber atrophy was present in 48% (n = 104/218) of biopsies, and was predominantly perifascicular in 19% (n = 6/31), with necrosis reported in 56% (n = 162/290) of cases. Sarcolemmal MHC-I upregulation was found in 72% (n = 64/89) of biopsies. Non-specified C5b-9 deposition was described in 39% of muscle biopsies (n = 28/72). Neurogenic features were present in 23% (n = 44/191); endomysial fibrosis was reported in 35% (n = 120/340); and rimmed vacuoles were observed in 32% (n = 11/34) of biopsies. Capillaropathy, such as capillary dropout and/or ultrastructural endothelial abnormalities, was reported in 33% (n = 43/129) of cases. Reported ENMC categories were mainly polymyositis (21%), non-specific myositis (19%), immune-mediated necrotizing myopathy (16%), and dermatomyositis (8%). Histopathological features were analyzed according to serological subtypes in 28 studies, including anti-PM-Scl (n = 48), -Ku (n = 23) and -U1RNP (n = 90). Most of these biopsies demonstrated inflammatory infiltrates (range 49–85%) as well as MHC-I expression (range 63–81%). Necrosis was associated with anti-Ku (85%) and anti-U1RNP (73%), while anti-Ku was also associated with neurogenic features and rimmed vacuoles in 57% and 25% of cases, respectively.ConclusionOur review suggests that SM is characterized by heterogeneous pathological features using definitions included in current histopathological criteria. Whether a distinct histopathological signature exists in SM remains to be determined. SSc-specific and SSc-associated autoantibodies may help define more homogeneous histopathological subsets.     

The mitochondrial seryl-tRNA synthetase SARS2 modifies onset in spastic paraplegia type 4

PurposeHereditary spastic paraplegia type 4 is extremely variable in age at onset; the same variant can cause onset at birth or in the eighth decade. We recently discovered that missense variants in SPAST, which influences microtubule dynamics, are associated with earlier onset and more severe disease than truncating variants, but even within the early and late-onset groups there remained significant differences in onset. Given the rarity of the condition, we adapted an extreme phenotype approach to identify genetic modifiers of onset.MethodsWe performed a genome-wide association study on 134 patients bearing truncating pathogenic variants in SPAST, divided into early- and late-onset groups (aged ≤15 and ≥45 years, respectively). A replication cohort of 419 included patients carrying either truncating or missense variants. Finally, age at onset was analyzed in the merged cohort (N = 553).ResultsWe found 1 signal associated with earlier age at onset (rs10775533, P = 8.73E-6) in 2 independent cohorts and in the merged cohort (N = 553, Mantel–Cox test, P < .0001). Western blotting in lymphocytes of 20 patients showed that this locus tends to upregulate SARS2 expression in earlier-onset patients.ConclusionSARS2 overexpression lowers the age of onset in hereditary spastic paraplegia type 4. Lowering SARS2 or improving mitochondrial function could thus present viable approaches to therapy.     

Health information exchange system usage patterns in three communities: Practice sites,users, patients,and data

ObjectivesPublic and private organizations are implementing systems for query-based health information exchange (HIE), the electronic aggregation of patient data from multiple institutions. However, existing studies of query-based HIE system usage have addressed a limited number of settings. Our goal was to quantify the breadth and depth of usage of a query-based HIE system implemented across multiple communities with diverse care settings and patient populations.MethodsWe performed a cross-sectional study in three communities in New York State using system access log files from January 2009 to May 2011 to measure usage patterns of a query-based HIE web portal system with respect to practice sites, users, patients, and data.ResultsSystem access occurred from 60% (n = 200) of practice sites registered to use the system in Community A, 59% (n = 156) in Community B, and 82% (n = 28) in Community C. In Communities A and B, users were primarily non-clinical staff in outpatient settings, while in Community C inpatient physicians were the main users. Across communities, proportions of patients whose data were accessed varied with 5% (n = 11,263) in Community A, 60% (n = 212,586) in Community B, and 1% (n = 1107) in Community C. In Community B, users updated patient consent through the HIE portal, whereas in the other communities, users updated patient consent through a separate system. Across communities, users most frequently accessed only patient summary data displayed by default followed by detailed laboratory and radiology data.ConclusionsThis study is among the first to illustrate large-scale usage of a query-based HIE system implemented across multiple communities. Patient summary data displayed by default may be an important feature of query-based HIE systems. User role, practice site type, and patient consent workflow may affect patterns of query-based HIE web portal system usage in the communities studied and elsewhere.