Interactions between iron and carbon in permafrost thaw ponds.

Thawing permafrost forms "thaw ponds" that accumulate and transport organic carbon (OC), redox-active iron (Fe), and other elements. Although Fe has been shown to act as a control on the microbial degradation of OC in permafrost soils, the role of iron in carbon cycling in thaw ponds remains poorly understood. Here, we investigated Fe-OC interactions in thaw ponds in partially and fully thawed soils ("bog" and "fen" thaw ponds, respectively) in a permafrost peatland complex in Abisko, Sweden, using size separation (large particulate fraction (LPF), small particulate fraction (SPF), and dissolved fraction (DF)), acid extractions, scanning electron microscopy (SEM), Fe K-edge X-ray absorption spectroscopy (XAS), and Fourier Transform Infrared (FTIR) spectroscopy. The bulk total Fe (total suspended Fe) in the bogs ranged from 135 mg/L (mean = 13 mg/L) whereas the fens exhibited higher total Fe (1.5 to 212 mg/L, mean = 30 mg/L). The concentration of bulk total OC (TOC) in the bog thaw ponds ranged from 50 to 352 mg/L (mean = 170 mg/L), higher than the TOC concentration in the fen thaw ponds (8.5 to 268 mg/L, mean = 17 mg/L). The concentration of 1 M HCl-extractable Fe in the bog ponds was slightly lower than that in the fens (93 ± 1.2 and 137 ± 3.5 mg/L Fe, respectively) with Fe predominantly (>75 %) in the DF in both thaw stages. Fe K-edge XAS analysis showed that while Fe(II) was the predominant species in LPF, Fe(III) was more abundant in the DF, indicating that the stage of thawing and particle size may control Fe redox state. Furthermore, Fe(II) and Fe(III) were partially complexed with natural organic matter (NOM, 8 to 80 %) in both thaw ponds. Results of our work suggest that Fe and OC released during permafrost thaw into thaw ponds (re-)associate, potentially protecting OC from microbial decomposition while also stabilizing the redox state of Fe.

Simulation of long-term impact of intravitreal anti-VEGF therapy on patients with severe non-proliferative diabetic retinopathy.

OBJECTIVE: A simulation model was constructed to assess long-term outcomes of proactively treating severe non-proliferative diabetic retinopathy (NPDR) with anti-vascular endothelial growth factor (anti-VEGF) therapy versus delaying treatment until PDR develops. METHODS AND ANALYSIS: Simulated patients were generated using a retrospective real-world cohort of treatment-naive patients identified in an electronic medical records database (IBM Explorys) between 2011 and 2017. Impact of anti-VEGF treatment was derived from clinical trial data for intravitreal aflibercept (PANORAMA) and ranibizumab (RISE/RIDE), averaged by weighted US market share. Real-world risk of PDR progression was modelled using Cox multivariable regression. The Monte Carlo simulation model examined rates of progression to PDR and sustained blindness (visual acuity <20/200) for 2 million patients scaled to US NPDR disease prevalence. Simulated progression rates from severe NPDR to PDR over 5 years and blindness rates over 10 years were compared for delayed versus early-treatment patients. RESULTS: Real-world data from 77 454 patients with mild-to-severe NPDR simulated 2 million NPDR patients, of which 86 680 had severe NPDR. Early treatment of severe NPDR with anti-VEGF therapy led to a 51.7% relative risk reduction in PDR events over 5 years (15 704 early vs 32 488 delayed), with a 19.4% absolute risk reduction (18.1% vs 37.5%). Sustained blindness rates at 10 years were 4.4% for delayed and 1.9% for early treatment of severe NPDR. CONCLUSION: The model suggests treating severe NPDR early with anti-VEGF therapy, rather than delaying treatment until PDR develops, could significantly reduce PDR incidence over 5 years and sustained blindness over 10 years.

Clinical Benefits of Treating Patients with Type 2 Diabetes Mellitus with iGlarLixi: A Patient-Level Simulation Study.

INTRODUCTION: The fixed-ratio combination of insulin glargine (iGlar) plus lixisenatide (iGlarLixi) has proven efficacious in clinical trials; however, there is limited evidence of its benefits in a variety of real-world patients with type 2 diabetes mellitus (T2DM) who present in routine clinical practice. METHODS: A large integrated claims and EHR database was used to identify two real-world (RW) cohorts (ages ≥ 18) with T2DM who were eligible for treatment with iGlarLixi. At baseline, the first cohort (insulin cohort) received insulin with or without oral antidiabetic drugs (OADs), and the second cohort (OAD-only cohort) received OADs only. A Monte Carlo patient-level simulation was applied to each cohort based on treatment strategies and efficacies from the LixiLan-L and LixiLan-O trials to estimate reductions in glycated hemoglobin A1C (A1C) and the percentage achieving age-based A1C goals (≤ 7% for ages < 65 and ≤ 8% for ages ≥ 65) at 30 weeks. RESULTS: The RW insulin (N = 3797) and OAD-only (N = 17,633) cohorts differed considerably in demographics, age, clinical characteristics, baseline A1C levels, and background OAD therapies compared to the populations in the Lixilan-L and Lixilan-O trials. Regardless of the cohort description, A1C goals were achieved among 52.6% vs. 31.6% (p < 0.001) of patients in the iGlarLixi vs. the iGlar arms in the insulin cohort simulation, while A1C goals were achieved among 59.9% vs. 49.3% and 32.8% (p < 0.001) of patients in the OAD-only cohort simulation in the iGlarLixi vs. the iGlar and lixisenatide arms, respectively. CONCLUSIONS: Irrespective of the treatment regimen at baseline (insulin vs. OAD only), this patient-level simulation demonstrated that a greater proportion of patients achieved their A1C goals with iGlarlixi compared to iGlar or lixisenatide alone. These findings suggest that the benefits of iGlarLixi extend to clinically distinct RW populations.

Modelling the potential long-term survival benefit of evinacumab treatment vs. standard of care in patients with homozygous familial hypercholesterolaemia.

AIMS: Despite intensive lipid-lowering therapies (LLTs), most patients with homozygous familial hypercholesterolaemia (HoFH) do not achieve guideline recommended low-density lipoprotein cholesterol (LDL-C) targets and are at increased risk of premature cardiovascular death. This analysis aimed to predict the impact of evinacumab and standard-of-care LLTs on life expectancy in an HoFH population using mathematical modelling. METHODS AND RESULTS: Mathematical models were developed using efficacy data for evinacumab from the phase 3 ELIPSE HoFH trial plus efficacy data for standard-of-care LLTs from peer-reviewed publications. Treatment strategies evaluated included (i) untreated, (ii) high-intensity statin (HIS) only, (iii) HIS plus ezetimibe, (iv) HIS plus ezetimibe plus proprotein convertase subtilisin/kexin type 9 inhibitor (PCSK9i), and (v) HIS plus ezetimibe plus PCSK9i plus evinacumab. Markov analyses were used to assess differences in survival probability for different LLT strategies. The median survival for untreated HoFH patients was only 33-43 years, depending on different assumptions on baseline untreated LDL-C levels. In the most robust model, we estimated that HIS increased median survival by 9 years and ezetimibe further increased median survival by an additional 9 years. When PCSK9i was added on top of HIS plus ezetimibe, median survival was further improved by 14 years. Finally, the addition of evinacumab to standard-of-care LLTs was estimated to increase median survival by ∼12 years. CONCLUSION: In this mathematical modelling analysis, evinacumab treatment could potentially increase long-term survival vs. standard-of-care LLTs for patients with HoFH.

This mathematical modelling analysis demonstrated that evinacumab in addition to standard-of-care lipid-lowering treatments (LLTs; high-intensity statin plus ezetimibe plus proprotein convertase subtilisin/kexin type 9 inhibitor) could increase long-term survival to a median of 77 years vs. the 65 years achieved with only standard-of-care LLTs in patients with homozygous familial hypercholesterolaemia.

Simulation of lipid-lowering therapy (LLT) intensification in very high-risk patients with atherosclerotic cardiovascular disease.

We aim to estimate the number and proportion of very-high risk patients with atherosclerotic cardiovascular disease (ASCVD) who would be able to achieve low-density lipoprotein cholesterol (LDL-C) <70 mg/dL with various lipid-lowering therapies (LLTs), including statins, ezetimibe, bempedoic acid, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, and evinacumab, using a Monte Carlo simulation model described previously. With current treatment options for LDL-C lowering, including statin, ezetimibe, bempedoic acid, and PCSK9 inhibitors, it was estimated that most very-high risk patients with ASCVD (99.1%) were able to achieve the LDL-C goal of <70 mg/dL. Nevertheless, approximately 88,715 patients in the USA were estimated to not be able to achieve the LDL-C goal after current available LLTs, thus remaining at elevated risk for recurrent cardiovascular events. Evinacumab may be useful to address such unmet needs effectively, as the majority of those not at goal after PCSK9 inhibitors could achieve the goal of <70 mg/dL after taking evinacumab.

Pathological Femoral Shaft Fracture With McCune-Albright Syndrome With Hyperthyroidism Managed With Oral Alendronate: A Case Report.

McCune-Albright syndrome (MAS) is a complex endocrinopathy with polyostotic fibrous dysplasia and café-au-lait spots. Pathological femoral shaft fracture along with MAS is not a common occurrence. Bisphosphonates can be used for the management of pathological fractures. A seven-year-old male child presented with pathological femoral shaft fracture with MAS (café-au-lait macules and hyperthyroidism). The patient was managed conservatively with closed reduction along with hip spica and oral alendronate. Fracture consolidation occurred within six to eight weeks with improvement in bone pains. Oral alendronate can be used as an adjuvant to conservative therapy for pathological fracture in MAS in children.

Lipid treatment status and goal attainment among patients with atherosclerotic cardiovascular disease in the United States: A 2019 update.

Objective: To update the prevalence of atherosclerotic cardiovascular disease (ASCVD) in the United States (US) and re-evaluate lipid-lowering therapies (LLT) utilization and low-density lipoprotein cholesterol (LDL-C) goal attainment among ASCVD patients after proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have become available using data from 2019. Methods: ASCVD patients with at least 1 valid LDL-C measurement from the 2019 Truven MarketScan Research Database were included and stratified into hierarchical cardiovascular risk groups. The number of patients in each group was extrapolated to approximate national figures based on national demographic and ASCVD prevalence numbers. Descriptive statistics on demographic and clinical characteristics, treatment status and LDL-C for each hierarchical category were reported. Results: The overall prevalence of ASCVD in the US in 2019 was 24.0 million, approximately 10% of the total US population above 21 years old. We found heavy comorbidity burden among ASCVD patients and 31.2% were at very high risk for recurrent events. The majority of ASCVD patients were not at guideline-recommended LDL-C goal. Although there was a significant increase in the use of LLTs (especially of high-intensity statins) in 2019 compared to 2014, overall LLT utilization remained low, with only 3.8% of ASCVD patients on ezetimibe, less than 1% on PCSK9 inhibitors and over 40% on no LLTs. We also found higher utilization of LLTs among patients who were at goal of < 70 or < 55 mg/dL vs. those not at goal. Conclusion: Despite an increase in high-intensity statins use since 2014, there was still an underutilization of LLTs in spite of evidence of their efficacy in LDL-C lowering and ability to reduce the risk of coronary heart disease. Increased awareness of guidelines by healthcare providers and urgency to treat ASCVD is needed in order to improve LLT utilization and help more patients reach the LDL-C goal.

Imaging Review of Pediatric Benign Osteocytic Tumors and Latest Updates on Management.

Pediatric benign osteocytic tumors include osteoma, enostosis, osteoid osteoma, and osteoblastoma. In pediatric populations, benign bone tumors are more common than malignancies. Benign osteocytic tumors may have a unique clinical presentation that helps narrow the differential diagnosis. A systemic imaging approach should be utilized to reach the diagnosis and guide clinicians in management. Radiographs are the most prevalent and cost-effective imaging modality. Cross-sectional imaging can be utilized for tissue characterization and for evaluation of lesions involving complex anatomical areas such as the pelvis and spine. Computed Tomography (CT) is the modality of choice for diagnosis of osteoid osteoma. CT scan can also be utilized to guide radiofrequency ablation, which has been found to be highly effective in treating osteoid osteoma and osteoblastoma. Enostosis is a no-touch lesion. Osteoma is commonly located in the paranasal sinuses. Osteoma needs an excision if it causes complications due to a mass effect.

Magnetic Resonance Imaging Appearance of Erythema Nodosum: A Case Report.

Erythema nodosum (EN) is the commonest inflammation of the subcutaneous fat tissue (panniculitis). Erythema nodosum (EN) requires an interdisciplinary approach and exclusion of all underlying causes. We present a case of an 18-year-old female with a history of recurrent streptococcal infections over the years, who developed pain and swelling in the left ankle. To evaluate the persistent ankle swelling, the physician ordered a magnetic resonance imaging (MRI) of the left lower extremity. The MRI appearance of EN has not been described in detail in the literature so far.

Dermoscopic Features of Nail Psoriasis: An Observational, Analytical Study.

INTRODUCTION: Nail involvement in psoriasis occurs in up to 30-50% of patients, and 5-10% may have isolated nail disease. Onychoscopy, a noninvasive tool, might obviate the need for nail biopsy, which is a diagnostic gold standard. OBJECTIVE: The aim of this study was to evaluate onychoscopic features of nail unit in patients with nail psoriasis. METHODS: Fifty-five patients with clinically diagnosed and histologically documented nail psoriasis were recruited. Onychoscopy was performed for each nail (excluding the 5th toenail). Clinically, 443/550 fingernails and 101/440 toenails were involved. The frequency distributions of various onychoscopic features was assessed and compared using the χ2 test (p value <0.05 was considered significant). RESULTS: With onychoscopy, additional 52 fingernails and 64 toenails showed psoriatic involvement. Pitting was the commonest finding in fingernails (60.5%) followed by subungual hyperkeratosis (SUH) (52.8%), onycholysis (40.8%), and dotted capillaries in hyponychium, proximal, and lateral nail folds (38.6 vs. 35.8 vs. 35.8%). In toenails, we observed SUH (85.1%), nail plate thickening (82.1%), onycholysis (77.2%), and dotted capillaries in hyponychium and nail folds (59.4 vs. 53.4 vs. 45.5%). Fuzzy lunula was a novel onychoscopic finding noted in 33.6% fingernails and 4.95% toenails (p < 0.00001). LIMITATIONS: Small sample size. CONCLUSIONS: Onychoscopy may aid in diagnosing nail lesions even before the clinical signs are apparent.

Genetic characterization and ex-vivo neutralization behavior of bluetongue virus serotype-16 recovered from apparently healthy goat.

Bluetongue virus (BTV) infects almost all the domestic and wild ruminants though the clinical disease is most commonly reported in sheep and some species of deer. Goat and cattle are the most common asymptomatic reservoir of the virus. Full genome sequencing and serological characterization of the virus isolates are emphasized for understanding the phylogenetic relationship and molecular epidemiology of bluetongue (BT). In this study, we report phylogenetic and phenotypic antigenic relationship of a BTV serotype-16 (PDP2/13/Ind) recovered from an apparently healthy goat from the state of Uttarakhand, a hilly terrain of sub-Himalayan India with four other BTV-16 isolates. The full genome sequence data was analyzed and the phylogenetic relationship of the goat isolate with other BTV-16 was established. Phylogenetic analysis revealed cluster of PDP2/13/Ind along with other Indian BTV-16 isolates indicating their close ancestral relationship. A cohesive ancestral relationship, irrespective of the genome segments analyzed, was also observed between Indian and Mediterranean BTV-16. The mean substitution rate of different segments of BTV-16 isolates varied from 3.231 × 10-5 (seg-2) to 1.129 × 10-3 (seg-6) substitutions per site per year. Timescale analysis indicated that all the segments had an older ancestor. No statistically significant geographic structuring of BTV-16 isolates was observed indicating frequent gene flow. The goat isolate shares highest identity (99.5%-99.8%) with G53/ABT/HSR, a BTV-16 recovered from the western part of the country whereas high level of divergence (11.9%-33.3%) at genomic segment level was observed with a Nigerian BTV-16 (NIG1982/10). Phenotypic antigenic relationship (r) of PDP2/13/Ind with other isolate-specific hyperimmune serum (HIS) determined from serum neutralization titer was 0.672 ± 0.058 to 0.948 ± 0.09. On other hand, the calculated 'r' score was 0.636 ± 0.063 to 0.814 ± 0.201 when HIS against PDP2/13/Ind was used to neutralize the other BTV-16 isolates. The percentage antigenic similarity (R) of the PDP2/13/Ind with other BTV-16 isolates was 65.39 ± 5.38-87.67 ± 14.86. Data suggests presence of subtype antigenic variation amongst the BTV-16 isolates recovered from the goats of a geographically restricted area of the state of Uttarakhand, India.

Seroprevalence of bluetongue and presence of viral antigen and type-specific neutralizing antibodies in goats in Tripura, a state at Indo-Bangladesh border of northeastern India.

Bluetongue (BT) is a notifiable multiple species transboundary viral disease of domestic and wild ruminants. Though the disease is enzootic in India, little is known of the disease burden and prevalent serotypes in Tripura, a hilly state of northeastern India sharing a vast porous border with Bangladesh. A surveillance study was conducted to understand the disease burden in goats in Tripura. Serum (n = 1240) and blood (n = 194) samples were collected during the year 2014 to 2017 from all the eight districts of Tripura. The overall prevalence of BT seroconversion was 47.58% whereas the presence of viral antigen was 20.61% at the individual level. Percent seroconversion was found more (50.47 ± 4.00, CI 41.31 to 49.47) in adult goats in comparison to the younger animals where it was 45.39 ± 2.08, CI 42.63 to 58.31. Presence of neutralizing antibodies in selected serum samples (n = 72) was investigated by serum neutralization test (SNT) against six bluetongue virus (BTV) serotypes and BTV-1 was found as most predominant (65.27%) followed by BTV-16 (26.38%), BTV-10 (20.83%), BTV-9 and 23 (13.88%), and BTV-2 (6.94%). To the best of our knowledge, this is the first study conducted in Tripura to investigate the presence of BTV antigen and type-specific neutralizing antibodies in apparently healthy goats.

Genetic and phylogenetic analysis of the outer capsid protein genes of Indian isolates of bluetongue virus serotype-16.

AIM: The aim of the study was to characterize bluetongue virus serotype 16 (BTV-16), recently isolated from different states of India. The evolutionary relationship of newly isolated BTV-16 and previously reported Indian and global BTV-16 isolates were compared using molecular analysis. MATERIALS AND METHODS: In the present study, five (n=5) BTV-16 isolates were used to amplify gene segment-2 and segment-6 encoding the outer capsid proteins VP2 and VP5, respectively. The amplified products were purified and sequenced by the Sanger sequencing method. The phylogenetic relationship and nucleotide identity of all five BTV-16 isolates were compared with previously reported Indian and global BTV-16 isolates. Nucleotide sequence data were aligned using the CLUSTAL W algorithm implemented in the MegAlign of DNASTAR program package (MegAlign 5.00, DNASTAR Inc., Madison, USA). Phylogenetic analyses were carried out using MEGA version 6.0 software with the best nucleotide substitution model. RESULTS: Phylogenetic analysis based on the VP2 and VP5 encoding genes, segregates Indian BTV-16 isolates in a distinct cluster with proximity to the Eastern topotype. Indian isolates make a monophyletic cluster with Eastern topotypes with Western topotype BTV-16 (BTV-16/NIG/AJ586694) occupying a separate cluster. Indian isolates were found to share 91.5%-97.5% and 96.5%-98.9% identity at the nucleotide and deduced amino acid (aa) level, respectively, to the global BTV-16 isolates. There is a high degree of variation with the Nigerian isolate with 27.0-27.7% and 26.0-26.9% at the nucleotide and aa sequence level, respectively. These data suggest that Indian BTV-16 isolates might have evolved separately within the Eastern BTV topotype. CONCLUSION: Phylogenetic analyses and nucleotide identity of BTV-16 isolates at the VP2 and VP5 gene encoded level indicate that isolates used in the present study might have evolved from a common Eastern topotype ancestor. The data presented in this study will be helpful for future selection of reference strains in a serological and molecular epidemiology study.

Interferon induced Mx protein from Indian snow trout Schizothorax richardsonii (Gray) lacks critical functional features unlike its mammalian homologues.

Viral attack within host cells triggers the production of type I interferons and leads to the induction of interferon stimulated genes (ISGs). One of the ISG Mx, encodes type I interferon inducible GTPase that is responsible for the establishment of an anti-viral state within cells. Intriguingly, several isoforms of Mx have been reported in fish, but the structural analysis of fish Mx proteins remains unexplored. For the first time, we have identified and unraveled the molecular structure of Mx protein from Indian snow trout, Schizothorax richardsonii (Gray) a Coldwater fish that inhabits the water bodies in the sub-Himalayan region. The snow trout Mx coding region consists of 2518 nucleotides with an open reading frame (ORF) of 1854 nucleotides. It codes for a polypeptide of 617 amino acids with a predicted molecular weight of 70 kDa. In silico analysis of snow trout Mx protein revealed signature of dynamin family (LPRGTGIVTR) along with a tripartite GTP-binding domain (GDQSSGKS, DLPG, and TKPD). Homology modelling established that the Mx protein is an elongated structure with a G domain, bundle signaling element (BSE) and a GTPase effector domain (GED). Moreover, the GED of Mx contains two highly conserved leucine zippers at the COOH-terminal of the protein suggesting its structural similarity with human homologues. However, snow trout Mx lacks the essential features of its mammalian homologues questioning its functional characteristics. Further, a ligand binding site in the said protein has also been predicted adjacent to the GTPase switch within the G domain.