Thirty-day mortality following surgical management of hip fractures during the COVID-19 pandemic: findings from a prospective multi-centre UK study.

PURPOSE: Thirty-day mortality of patients with hip fracture is well researched and predictive; validated scoring tools have been developed (Nottingham Hip Fracture Score, NHFS). COVID-19 has significantly greater mortality in the elderly and comorbid patients which includes hip fracture patients. Non-operative treatment is not appropriate due to significantly higher mortality, and therefore, these patients are often exposed to COVID-19 in the peri-operative period. What is unclear is the effect of concomitant COVID-19 infection in these patients. METHODS: A multicentre prospective study across ten sites in the United Kingdom (responsible for 7% of hip fracture patients per annum in the UK). Demographic and background information were collected by independent chart review. Data on surgical factors included American Society of Anesthesiologists (ASA) score, time to theatre, Nottingham Hip fracture score (NHFS) and classification of fracture were also collected between 1st March 2020 and 30th April 2020 with a matched cohort from the same period in 2019. RESULTS: Actual and expected 30-day mortality was found to be significantly higher than expected for 2020 COVID-19 positive patients (RR 3.00 95% CI 1.57-5.75, p < 0.001), with 30 observed deaths compared against the 10 expected from NHFS risk stratification. CONCLUSION: COVID-19 infection appears to be an independent risk factor for increased mortality in hip fracture patients. Whilst non-operative management of these fractures is not suggested due to the documented increased risks and mortality, this study provides evidence to the emerging literature of the severity of COVID-19 infection in surgical patients and the potential impact of COVID-19 on elective surgical patients in the peri-operative period.

Correction to: Thirty-day mortality following surgical management of hip fractures during the COVID-19 pandemic: findings from a prospective multi-centre UK study.

The published online version contains mistake, as the Fig. 1 legend should read "Kaplan-Meier survival curve for 30-day survival for 2020 cohort COVID-19 positive vs COVID-19 negative" whilst the Fig. 2 legend should read "Kaplan-Meier survival curve for 30-day survival 2020 COVID-19 negative group vs 2019 cohort".

Impact of functional IL-18 polymorphisms on genetic predisposition and diverse clinical manifestations of the disease in Indian SLE patients.

Several studies have demonstrated associations between interleukin-18 polymorphisms and risk of systemic lupus erythematosus in different populations except one of Indian origin. We therefore investigated for the influence of interleukin-18 (-1297T/C, -607A/C, -137G/C; + 105A/C) polymorphisms on genetic susceptibility and clinical expression of the disease in Indian systemic lupus erythematosus patients. A total of 200 systemic lupus erythematosus patients and 201 controls were recruited. Genotyping of interleukin-18 polymorphisms were performed by polymerase chain reaction-restriction fragment length polymorphism. Serum interleukin-18 levels were measured by enzyme-linked immunosorbent assay. Interleukin-18 (-1297T/C; -137G/C) polymorphisms showed significant association with genetic susceptibility to the disease in our systemic lupus erythematosus cohort. Stratification analysis revealed -1297CC and -1297C associated with renal involvement (odds ratio = 3.4, correcting p value = 0.0207), (odds ratio = 2.0, correcting p value = 0.0054) respectively. Additionally, -1297C allele frequency was significantly increased in patients with anti-nucleosome antibody (odds ratio = 2.1, correcting p value = 0.0301). Haplotype analysis showed CC haplotype strongly associated with serositis (odds ratio = 9.1, correcting p values = 0.0009) and neurologic involvement (odds ratio = 9.3, correcting p value = 0.0018). We reported a 2.7-fold increase in serum interleukin-18 levels in patients (511.5 ± 242.3 pg/ml) compared to controls (189.4 ± 80.8 pg/ml) ( p < 0.0001). Furthermore, interleukin-18 levels were positively correlated with disease activity ( r = 0.548, p = 0.0001) and renal involvement in the patients with lupus nephritis ( r = 0.569, p < 0.0001). In summary, interleukin-18 polymorphisms elucidated in this study appear to confer genetic susceptibility to the disease and are associated with renal, serositis and neurologic involvement in Indian systemic lupus erythematosus patients.

Indeterminate nodules in osteosarcoma: what's the follow-up?

BACKGROUND: Indeterminate pulmonary nodules in patients diagnosed with osteosarcoma present a challenge for accurate staging and prognosis. The aim of this study was to explore the significance of this finding. METHODS: A retrospective cohort study of 120 patients with osteosarcoma was performed in the North East of England. Chest computed tomographies (CTs) at presentation were reviewed and the incidence of 'indeterminate' nodules recorded. Follow-up scans were reviewed and survival as well as prognostic features were analysed. RESULTS: 25% of our cohort presented with indeterminate nodules. Of these, 33% were subsequently confirmed as metastases, the majority within a year. Kaplan-Meier survival analysis showed that patients with indeterminate nodules fared better than those with frank metastatic disease, and similar to those who presented with a normal chest CT. We found no radiographic features that predicted survival. CONCLUSIONS: Indeterminate nodules remain a clinical and diagnostic dilemma. Close monitoring of patients is advised during the first year from presentation, and there is potential for indeterminate nodules to develop into frank metastases later than five years from presentation.

Circulating microfilariae in haematological malignancies: do they have a role in pathogenesis?

Filariasis is very common in tropical countries. It is endemic in the coastal areas of India. We report four cases of haematological malignancy where peripheral blood and bone marrow smears did not show any microfilariae but conventional cytogenetic preparations from all the four cases showed the presence of parasites. Their morphology confirmed the diagnosis of all cases as bancroftian filariasis. Therefore all types of cytogenetic preparations should be screened carefully in the endemic areas along the coastal zones of India for the presence of this parasite.

Aromatase expression in atypical ductal hyperplasia in women.

PURPOSE: To determine the levels of aromatase in atypical ductal hyperplasia (ADH) lesions, tissue surrounding the ADH, and in dense and non-dense normal breast tissue. We postulated that excess aromatase in breast tissue might, through production of increased estrogen, drive the carcinogenic process. Estrogens and their metabolites are thought to contribute to the development of breast cancer through estrogen receptor-mediated mechanisms and genotoxic effects of estrogen metabolites. ADH is a benign lesion of the breast which is associated with substantially increased risk for subsequent development of breast cancer. After 25 years, approximately 30% of women with ADH develop breast cancer. In women with three or more separate ADH lesions at the same time, 47% will develop breast cancer over that time period. Another important risk factor for breast cancer is the presence of mammographically dense breast tissue. METHODS: We utilized quantitative immunochemical analysis of aromatase in biopsy tissue to test this possibility. Previously published results comparing dense with non-dense breast tissue in normal women (Vachon et al. Breast Cancer Res Treat 125:243-252, 2011) were used for comparisons with ADH. A well-characterized histochemical H-score was employed for quantitative assessment of aromatase in the various tissue studied. RESULTS: The H-score of aromatase staining was statistically significantly higher (p = 0.003) in the ADH epithelium than surrounding epithelial tissue. In order of H-score from highest to lowest were ADH, issue surrounding ADH, dense normal and non-dense normal breast tissues. The levels of aromatase in a subset of women with ADH who went on to develop breast cancer were not higher than in women who did not. CONCLUSIONS: We suggest from these studies that overexpression of aromatase in breast tissue and its resultant increase in estradiol levels may contribute to the later development of breast cancer in women with ADH.

Role of MMP-7 in the pathogenesis of systemic lupus erythematosus (SLE).

Systemic lupus erythematosus (SLE) is a clinically heterogeneous chronic, inflammatory autoimmune disorder. The association of MMP-7 and disease severity is still unclear. A total of 150 SLE patients and matched healthy controls were recruited for this study. Disease activity was scored according to SLEDAI (98 active and 52 inactive disease). Mean serum MMP-7 levels were significantly higher in SLE patients than controls ( p < 0.001). Patients with active disease showed higher levels (16.24 ± 6.2 ng/ml) as against inactive disease (10.50 ± 3.97 ng/ml) ( p ≤ 0.0001). Mean MMP-7 mRNA expression was significantly higher in patients (RQ = 3.16 ± 0.93) as compared to controls (RQ = 2.21 ± 0.89, p = 0.006). A positive correlation between MMP-7 levels, mRNA expression and SLEDAI score was observed ( r = 0.563, r = 0.427). The MMP-7 -181 G allele was found to be significantly higher among SLE patients ( p < 0.0001). A significant association was noted between MMP-7 -181 A/G +G/G genotypes with renal ( p = 0.0027) and CNS ( p = 0.0031) manifestations and anti-dsDNA autoantibodies ( p = 0.0312). Serum MMP-7 levels and mRNA expression were elevated in advanced stages of SLE, indicating that MMP-7 is associated with disease activity in SLE.

Synergistic effect of two ß globin gene cluster mutations leading to the hereditary persistence of fetal hemoglobin (HPFH) phenotype.

Co-inheritance of gamma and beta globin gene mutations in a compound heterozygous state is rare but of clinical interest as it provides an important data on understanding the HbF expression. Hematological analysis was carried out (Sysmex KX-21). F-cells were enumerated using flow cytometry. Beta globin gene was analysed by CRDB technique and by DNA sequencing. Gamma globin promoter region was sequenced and expression studies were carried out using real time Taqman assay. We report a family, where two inherited defects of the ß globin gene cluster segregate. The proband and her sibling were compound heterozygotes for a novel Gγ promoter mutation and the 619 bp deletion a common Indian ß thalassemia mutation. Molecular characterization revealed that the father (HbA2 5.1%, HbF 5.4%), proband (HbA2 3.6%, HbF 31.7%) and her brother (HbA2 3.9%, HbF 23.6%) were heterozygous for the 619 bp deletion. The mother (HbA2 2.1%, HbF 3.4%) had a normal ß globin gene. As both the children showed high HbF levels, the γ globin gene work up was carried out. The Gγ-globin gene promoter analysis revealed that the mother and the two children were heterozygous for a 5 bp deletion -ATAAG (-533 to -529) that resides in the GATA binding site. These findings suggest that the 5 bp deletion in the Gγ globin promoter has a functional role in silencing the γ-globin gene expression in adults by disrupting GATA-1 binding and the associated repressor complex and results in the up-regulation of gamma globin gene expression. When co-inherited with ß -thalassemia trait it leads to a phenotype of HPFH.

Do high sensitivity C-reactive protein and serum interleukin-6 levels correlate with disease activity in systemic lupus erythematosuspatients?

INTRODUCTION: Systemic Lupus Erythematosus (SLE) is an inflammatory autoimmune disease where an interplay between acute phase proteins and cytokines are involved in disease activation. AIM AND OBJECTIVES: This case control study was performed to investigate interrelationship between high sensitivity C-reactive proteins (hs-CRP), Interleukin-6 (IL-6) levels and disease activity among SLE patients. MATERIALS AND METHODS: One hundred forty one clinically diagnosed SLE cases were included and disease activity was noted by SLE Disease Activity Index (SLEDAI). Serum IL-6 levels were measure by cytokine multiplex assay. Serum hs-CRP, C3 and C4 levels were measure by nephelometer. The Pearson correlation test was used for correlation between hs-CRP, Il-6 and SLEDAI. RESULTS: Based on SLEDAI, 126 patients (89.4 %) had active disease and 15 patients (10.6%) had inactive disease. Mean hs-CRP levels in SLE patients were significantly higher (12.1+ 11.5 mg/L) than controls (2.41+ 1.37 mg/L) (P < 0.0001). Hs-CRP levels among active SLE were significantly higher (13.5+ 11.4 mg/L) as compared with inactive SLE (4.4 + 2.9 mg/L) (P=0.0002). Similarly, IL-6 levels in SLE patients were significantly higher among active SLE (26.9 + 15.5 pg/ml) as compared with inactive SLE (13.9+ 10.2 pg/ml) (P=0.0001). An inverse correlation between Il-6 and hemoglobin levels between active and inactive SLE was noted (r=-0.46, P <0.0001). CONCLUSION: This study suggests a good correlation between hs-CRP, IL-6 and SLE disease activity indicating their direct involvement in inflammatory conditions associated with disease.

Annexin A5 levels or circulating microparticles: what we see depends mainly on what we look for.

Click here to view the article Letter to the Editor by C. Reutelingsperger et al.

Virtual analysis of structurally diverse synthetic analogs as inhibitors of snake venom secretory phospholipase A2.

Due to the toxic pathophysiological role of snake venom phospholipase A2 (PLA2 ), its compelling limitations to anti-venom therapy in humans and the need for alternative therapy foster considerable pharmacological interest towards search of PLA2 specific inhibitors. In this study, an integrated approach involving homology modeling, molecular dynamics and molecular docking studies on VRV-PL-V (Vipera russellii venom phospholipase A2 fraction-V) belonging to Group II-B secretory PLA2 from Daboia russelli pulchella is carried out in order to study the structure-based inhibitor design. The accuracy of the model was validated using multiple computational approaches. The molecular docking study of this protein was undertaken using different classes of experimentally proven, structurally diverse synthetic inhibitors of secretory PLA2 whose selection is based on IC50 value that ranges from 25 µM to 100 µM. Estimation of protein-ligand contacts by docking analysis sheds light on the importance of His 47 and Asp 48 within the VRV-PL-V binding pocket as key residue for hydrogen bond interaction with ligands. Our virtual analysis revealed that compounds with different scaffold binds to the same active site region. ADME analysis was also further performed to filter and identify the best potential specific inhibitor against VRV-PL-V. Additionally, the e-pharmacophore was generated for the best potential specific inhibitor against VRV-PL-V and reported here. The present study should therefore play a guiding role in the experimental design of VRV-PL-V inhibitors that may provide better therapeutic molecular models for PLA2 recognition and anti-ophidian activity.

Congenital macrothrombocytopenia is a heterogeneous disorder in India.

INTRODUCTION: Inherited macrothrombocytopenia represents a heterogeneous group of disorders which are characterized by the presence of a reduced number of abnormally large platelets in the circulation, which may or may not be associated with a bleeding tendency. In spite of several causative genes having been identified, the underlying genetic defects remain to be identified in approximately half of the cases. AIMS: To understand the molecular pathology of isolated giant platelet disorder from India. MATERIALS AND METHODS: We studied 112 cases that were referred for investigation of macrothrombocytopenia. Agonist induced platelet aggregation and platelet GP1b/IX/V receptor expression were investigated to assess GP1b/IX/V receptor expression and the GP1BA, GP1BB, GP9, ABCG5, ABCG8, TUBB1 and MYH9 genes were analysed to identify candidate gene defects. RESULTS: Twenty-three candidate gene defects were identified in 48 of 112 cases, 20 of which were novel. Of the candidate defects identified, 91% were missense and 9% were nonsense variations. The missense variations were in GP9 (9), ABCG5 (4), GP1BB (3), GP1BA (3) and MYH9 (2), while the nonsense defects occurred in MYH9 (1) and GP1BA (1). CONCLUSIONS: This study increases the understanding of the molecular basis of an isolated giant platelet disorder, a common heterogeneous condition prevalent in north and eastern India.

Amnion Epithelial Cells of Buffalo (Bubalus Bubalis) Term Placenta Expressed Embryonic Stem Cells Markers and Differentiated into Cells of Neurogenic Lineage In Vitro.

Aim of the present study was the isolation, culture, and characterization of amniotic membrane-derived epithelial cells (AE) from term placenta collected postpartum in buffalo. We found that cultured cells were of polygonal in shape, resistance to trypsin digestion and expressed cytokeratin-18 indicating that they were of epithelial origin. These cells have negative expression of mesenchymal stem cell markers (CD29, CD44, and CD105) and positive for pluripotency marker (OCT4) genes indicated that cultured cells were not contaminated with mesenchymal stem cells. Immunofluorescence staining with pluripotent stem cell surface markers, SSEA-1, SSEA-4, TRA-1-60, and TRA-1-81 indicated that these cells may retain pluripotent stem cell characteristics even after long period of differentiation. Differentiation potential of these cells was determined by their potential to differentiate into cells of neurogenic lineages using retinoic acid. In conclusion, we demonstrate that AE cells expressed pluripotent stem cell markers and have propensity to differentiate into cells of neurogenic lineage upon directed differentiation in vitro.

Conduction Mechanisms in CVD-Grown Monolayer MoS2 Transistors: From Variable-Range Hopping to Velocity Saturation.

We fabricate transistors from chemical vapor deposition-grown monolayer MoS2 crystals and demonstrate excellent current saturation at large drain voltages (Vd). The low-field characteristics of these devices indicate that the electron mobility is likely limited by scattering from charged impurities. The current-voltage characteristics exhibit variable range hopping at low Vd and evidence of velocity saturation at higher Vd. This work confirms the excellent potential of MoS2 as a possible channel-replacement material and highlights the role of multiple transport phenomena in governing its transistor action.

Association of Serum Ferritin Levels with Hematological Manifestations in Systemic Lupus Erythematosus Patients from Western India.

OBJECTIVE: To identify the hematological manifestations and its association with serum ferritin levels in SLE patients from Western India. METHODS: Ninety clinically diagnosed SLE patients fulfilling ACR criteria were included. Disease activity was assessed at the time of evaluation using Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). Sera were tested for serum ferritin levels by ELISA (Calbiotech, USA). Autoantibodies such as ANA, anti-dsDNA by indirect immunofluorescence test (IFA- Bio-Rad, USA) and anti-cardiolipin antibodies (ACA) to IgG and IgM isotypes and Anti-ß2 GP antibodies to IgG and IgM isotypes were detected by ELISA using commercially available kits (Euroimmun, Lubeck, Germany). RESULTS: Out of 90 SLE patients studied, 41 patients (45.6%) showed hematological abnormalities, where anemia (82.9%), leucopenia (26.8%), autoimmune hemolytic anemia (AIHA) (14.6%) and idiopathic thrombocytopenic purpura (ITP) were noted in (34.1%) patients. Mean±SD serum ferritin levels among SLE patients were 270.2±266.0 ng/ml as compared to 29.0±15.8 ng/ml healthy normal controls (p<0.0001). A positive correlation between serum ferritin levels and SLEDAI scores (r= 0.2640, p=0.0124) and anti-dsDNA positivity was noted (r=0.32, p<0.0001). Serum ferritin levels were negatively correlated with hemoglobin levels (r=-0.5964, p=0.0001), WBC count (r=-0.1705, p=0.2316), platelet count ((r=-0.1701, P=0.2375), C3 levels (r=-0.4417, p=0.0034) and C4 levels (r=-0.0363, p=0.8215). CONCLUSIONS: Serum ferritin is an excellent marker of SLE which can be used for an evaluation of disease activity particularly in active stage of the disease mainly in patients having hematological and renal manifestations.

B7x/B7-H4 modulates the adaptive immune response and ameliorates renal injury in antibody-mediated nephritis.

Kidney disease is one of the leading causes of death in patients with lupus and other autoimmune diseases affecting the kidney, and is associated with deposition of antibodies as well as infiltration of T lymphocytes and macrophages, which are responsible for initiation and/or exacerbation of inflammation and tissue injury. Current treatment options have relatively limited efficacy; therefore, novel targets need to be explored. The co-inhibitory molecule, B7x, a new member of the B7 family expressed predominantly by non-lymphoid tissues, has been shown to inhibit the proliferation, activation and functional responses of CD4 and CD8 T cells. In this study, we found that B7x was expressed by intrinsic renal cells, and was up-regulated upon stimulation with inflammatory triggers. After passive administration of antibodies against glomerular antigens, B7x(-/-) mice developed severe renal injury accompanied by a robust adaptive immune response and kidney up-regulation of inflammatory mediators, as well as local infiltration of T cells and macrophages. Furthermore, macrophages in the spleen of B7x(-/-) mice were polarized to an inflammatory phenotype. Finally, treatment with B7x-immunoglobulin (Ig) in this nephritis model decreased kidney damage and reduced local inflammation. We propose that B7x can modulate kidney damage in autoimmune diseases including lupus nephritis and anti-glomerular basement membrane disease. Thus, B7x mimetics may be a novel therapeutic option for treatment of immune-mediated kidney disease.