The pandemic is gone but its consequences are here to stay: avascular necrosis following corticosteroids administration for severe COVID-19.

BACKGROUND: In patients with COVID-19 infection and respiratory insufficiency, corticosteroid (CCS) administration is recommended. Among the wide range of complications and interactions, time-limited high-dose CCS administration might promote avascular necrosis (AVN) in a cumulative dose. This systematic review updated the current evidence and characterises the trend of AVN following time-limited high-dose CCS administration in patients who had severe COVID-19, discussing management strategies and outcomes. METHODS: This systematic review was conducted according to the 2020 PRISMA statement. In October 2023, the following databases were accessed: PubMed, Web of Science, Google Scholar, and Scopus restricting the search to the years 2019 to 2023. All the clinical studies which investigated the association between time-limited high-dose CCS administration in patients with severe COVID-19 infection and AVN were accessed. RESULTS: A total of 245 patients (9 studies) who experienced AVN following COVID-19 were included in the present investigation. 26% (63 of 245 included patients) were women. The mean age of the patients was 42.9 ± 17.7 years. Four studies focused on AVN of the hip and two on the knee, and the other studies included patients with AVN from mixed areas of the body (spine, pelvis, and shoulder). The mean time elapsed from COVID-19 infection to the development of symptomatic AVN was 79.4 ± 59.2 days (range, 14 to 166 days). CONCLUSION: It is possible that even time-limited high-dose CCS administration in patients with severe COVID-19 infection increased the incidence of AVN. The mean time elapsed from COVID-19 infection to the development of symptomatic AVN was approximately 80 days. Given the high risk of bias in all the included studies, the quality of recommendations of the present investigation is low, and no reliable conclusion can be inferred.

A Tertiary Care Centre Experience of Recurrent Giant Cell Tumor Around the Knee Joint.

INTRODUCTION: Giant cell tumor (GCT) is a benign but locally aggressive bone tumor. It has a peak incidence between 30-40 years with a predilection for the epiphyseal/metaphyseal region of bone. The most common locations for bone GCT are the distal femur, proximal tibia, distal radius, and sacrum in decreasing order. MATERIAL AND METHODS: In this retrospective study, 22 patients (13 females and nine males) with recurrent giant cell tumors around the knee joint between 2009-2022, with a mean age of 30.2 years (range: 18-55) were included. The patients were followed up monthly for three months, three-monthly for the next two years, six-monthly for the next five years, and thereafter, yearly. The mean follow-up period was 36.97 months (range 23-120 months). RESULTS: There were 19 recurrences after curettages and three after resections. Re-extended curettage was done in 17 cases and the resultant cavities were filled with autologous bone grafts in six and with polymethyl methacrylate (PMMA) cement in the other 11 cases. Reconstruction with megaprosthesis was done in two patients whereas knee arthrodesis was done in two patients after wide resection. The average Musculoskeletal Tumor Society (MSTS) score of our series of 22 patients was 23.1 (Range: 19-30). CONCLUSION: Campanacci grade 1 and 2 lesions can be successfully treated with extended curettage and bone grafting/bone cementing. For patients with grade 3 lesions, there are two options available according to the financial status of the patient; the first option is reconstruction with prosthesis and the other option is arthrodesis.

Recurrent Giant Cell Tumour of Distal End Radius: Treatment and Outcomes After Further Surgeries.

INTRODUCTION: Distal end radius is the second most common location for giant cell tumours (GCTs) followed by the knee. Like at any other location, they are treated with extended curettage or resection but reportedly have an increased propensity for recurrence. This study aims to treat the recurrent distal end radius GCTs and their outcome after further surgeries. PATIENTS AND METHODS: This study was conducted retrospectively from 2009 to 2021 and included 32 patients with recurrent distal end radius GCTs with a mean age of 29.53 years (range: 18-45 years). Twenty-five recurrences occurred after curettage and seven after resection. Twelve lesions were treated with further extended curettage. Nineteen recurrent lesions were treated with resection and arthrodesis. One out of two soft tissue recurrences was treated with en bloc resection. The mean follow-up period was 45.25 months (range: 24-120). RESULTS: The patients with joint preservations treated with further curettage and those where resection of soft tissue recurrences was done with salvage of joint had better functional outcomes with a mean Musculoskeletal Tumor Society (MSTS) score of 26.53 (Range: 22-30). The cases with arthrodesis had an average score of 23.75 (Range: 20-26). The overall average MSTS score was 24.89. CONCLUSIONS: We conclude that local recurrence contained within the bone can be re-curetted. The isolated soft tissue recurrences can be re-excised. The bony lesions with extensive soft tissue extension should be treated with resection and reconstruction. The re-recurrence rate after further adequate treatment does not increase much.

Outcomes of Wide Resection of Soft-Tissue Sarcoma of the Extremity: A Retrospective Analysis.

Background Soft-tissue sarcomas (STSs) are a rare heterogeneous group of tumors. Good functional results can be achieved with tumor excision in combination with suitable supplemental adjuvant therapies if needed. This study aimed to investigate the outcomes of wide resection of STS of the extremities. Methodology In this retrospective study, a total of 139 patients diagnosed with STS of the extremities by radiological and/or histopathological study/biopsy were included. All patients irrespective of metastasis were included. Results The mean age of the patients in our study was 43.5 ± 18.89 years. Overall, the mean tumor size was found to be 11.81 ± 6.218 cm. Malignant fibrous histiocytoma was the most common histology encountered (41%). Synovial sarcoma was the second most common histology encountered (14.38%). Recurrence was observed in 14 (10.1%) patients. The overall survival was 64.7% in our study. Conclusions The surgical margin achieved during the surgery is the most detrimental factor in local tumor control, and the overall survival of the patient after resection mainly depends on the stage of the tumor.

Identification and characterization of novel infection associated transcripts in macrophages.

By analysis of lncRNA expression profiles of macrophages in response to Mycobacterium tuberculosis (Mtb) infection, we identified novel highly expressed transcripts, unique in encompassing a protein coding transcript- Cytidine Monophosphate Kinase 2 (CMPK2) and a previously identified lncRNA- Negative Regulator of Interferon Response (NRIR). While these transcripts (TILT1, 2,3 - TLR4 and Infection induced Long Transcript) are induced by virulent Mtb as well as lipopolysaccharide (LPS) early, lack of/delayed expression in non-viable Mtb/BCG infected cells, respectively, suggest an important role in macrophage responses. The elevated expression by 3 hr in response to fast growing bacteria further emphasizes the importance of these RNAs in the macrophage infection response. Overall, we provide evidence for the presence of multiple transcripts that form a part of the early infection response programme of macrophages.Abbreviations: IFN: Interferon; NRIR: negative regulator of interferon response; CMPK2: cytidine/ uridine monophosphate kinase; LPS: lipopolysaccharide; LAM: Lipoarabinomannan; PIMs: Phosphatidylinositol Mannosides; TILT1, 2,3: TLR4 and Infection induced Long Transcript; TLR4: Toll-like receptor 4; Mtb: Mycobacterium tuberculosis; BCG: Mycobacterium bovis BCG; MDMs: human monocyte derived macrophages.

Immunophenotyping and Transcriptional Profiling of Human Plasmablasts in Dengue.

Plasmablasts represent a specialized class of antibody-secreting effector B cells that transiently appear in blood circulation following infection or vaccination. The expansion of these cells generally tends to be massive in patients with systemic infections such as dengue or Ebola that cause hemorrhagic fever. To gain a detailed understanding of human plasmablast responses beyond antibody expression, here, we performed immunophenotyping and RNA sequencing (RNA-seq) analysis of the plasmablasts from dengue febrile children in India. We found that plasmablasts expressed several adhesion molecules and chemokines or chemokine receptors that are involved in endothelial interactions or homing to inflamed tissues, including skin, mucosa, and intestine, and upregulated the expression of several cytokine genes that are involved in leukocyte extravasation and angiogenesis. These plasmablasts also upregulated the expression of receptors for several B-cell prosurvival cytokines that are known to be induced robustly in systemic viral infections such as dengue, some of which generally tend to be relatively higher in patients manifesting hemorrhage and/or shock than in patients with mild febrile infection. These findings improve our understanding of human plasmablast responses during the acute febrile phase of systemic dengue infection. IMPORTANCE Dengue is globally spreading, with over 100 million clinical cases annually, with symptoms ranging from mild self-limiting febrile illness to more severe and sometimes life-threatening dengue hemorrhagic fever or shock, especially among children. The pathophysiology of dengue is complex and remains poorly understood despite many advances indicating a key role for antibody-dependent enhancement of infection. While serum antibodies have been extensively studied, the characteristics of the early cellular factories responsible for antibody production, i.e., plasmablasts, are only beginning to emerge. This study provides a comprehensive understanding of the transcriptional profiles of human plasmablasts from dengue patients.

Chikungunya-specific IgG and neutralizing antibody responses in natural infection of Chikungunya virus in children from India.

Chikungunya virus (CHIKV) infection is endemic in many different countries. CHIKV outbreaks are emerging in new areas and re-emerging in previously exposed geographical regions, thus making it a significant public health concern. CHIKV infections are often clinically inapparent, especially in children, which poses a challenge to testing and evaluating any vaccine. During CHIKV infection, CHIKV-specific antibodies are produced, and some of these antibodies can neutralize viruses released from infected cells before they can enter uninfected cells. In this study, we evaluated IgG binding and neutralizing antibody responses in paired serum samples from CHIKV-infected children and those with other febrile illness, using a recombinant truncated E2 protein and whole CHIKV particles as test antigens. Antibody detection using the truncated E2 protein showed a significant overlap between CHIKV-infected subjects and those with other febrile illnesses. This overlap was greater when binding antibody titers were determined using fixed CHIKV particles as the test antigen. Acute- and convalescent-phase sera collected from children after CHIKV infection showed significant differences in their neutralizing capacity. The neutralizing and binding antibody response showed a significant positive correlation. We detected IgG antibodies in most cases during the acute phase of infection. This was observed at two different geographical locations, one of which is not considered highly endemic. Conventional wisdom would suggest this to be a marker of re-infection (secondary infection). However, dissenting opinions have been voiced in other viral diseases (such as Ebola) where studies have detected IgG in acute illness. In the absence of any significant body of work documenting secondary CHIKV infections, we believe further work is needed to understand the early IgG response that we observed.

Respiratory Syncytial Virus-Induced Oxidative Stress Leads to an Increase in Labile Zinc Pools in Lung Epithelial Cells.

Zinc supplementation in cell culture has been shown to inhibit various viruses, like herpes simplex virus, rotavirus, severe acute respiratory syndrome (SARS) coronavirus, rhinovirus, and respiratory syncytial virus (RSV). However, whether zinc plays a direct antiviral role in viral infections and whether viruses have adopted strategies to modulate zinc homeostasis have not been investigated. Results from clinical trials of zinc supplementation in infections indicate that zinc supplementation may be beneficial in a pathogen- or disease-specific manner, further underscoring the importance of understanding the interaction between zinc homeostasis and virus infections at the molecular level. We investigated the effect of RSV infection on zinc homeostasis and show that RSV infection in lung epithelial cells leads to modulation of zinc homeostasis. The intracellular labile zinc pool increases upon RSV infection in a multiplicity of infection (MOI)-dependent fashion. Small interfering RNA (siRNA)-mediated knockdown of the ubiquitous zinc uptake transporter ZIP1 suggests that labile zinc levels are increased due to the increased uptake by RSV-infected cells as an antiviral response. Adding zinc to culture medium after RSV infection led to significant inhibition of RSV titers, whereas depletion of zinc by a zinc chelator, N,N,N',N'-tetrakis(2-pyridinylmethyl)-1,2-ethanediamine (TPEN) led to an increase in RSV titers. The inhibitory effect of zinc was specific, as other divalent cations had no effect on RSV titers. Both RSV infection and zinc chelation by TPEN led to reactive oxygen species (ROS) induction, whereas addition of zinc blocked ROS induction. These results suggest a molecular link between RSV infection, zinc homeostasis, and oxidative-stress pathways and provide new insights for developing strategies to counter RSV infection.IMPORTANCE Zinc deficiency rates in developing countries range from 20 to 30%, and zinc supplementation trials have been shown to correct clinical manifestations attributed to zinc deficiency, but the outcomes in the case of respiratory infections have been inconsistent. We aimed at understanding the role of zinc homeostasis in respiratory syncytial virus (RSV) infection. Infection of lung epithelial cell lines or primary small-airway epithelial cells led to an increase in labile zinc pools, which was due to increased uptake of zinc. Zinc supplementation inhibited RSV replication, whereas zinc chelation had an opposing effect, leading to increases in RSV titers. Increases in labile zinc in RSV-infected cells coincided with induction of reactive oxygen species (ROS). Both zinc depletion and addition of exogenous ROS led to enhanced RSV infection, whereas addition of the antioxidant inhibited RSV, suggesting that zinc is part of an interplay between RSV-induced oxidative stress and the host response to maintain redox balance.

Impact of HIV infection and highly active antiretroviral therapy (HAART) on B cell subpopulations in children.

B-cells play an important role in defending children against various infections. In view of scare data, we undertook this prospective cohort study to describe B cell compartment in HIV infected children (<5 years of age) and the effect of HAART on B cell subpopulations. HIV infected children (<5 years) from Pediatric HIV services of the Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, were recruited (April 2012-December 2015). The enrolled HIV-1 infected children (n = 59) were followed up regularly for 12 months; healthy controls (n = 51) included HIV uninfected children with no major illness. Flow cytometry was performed on fresh EDTA-treated blood samples to characterize B cell subpopulations. In HIV-infected children, marked depletion of naive (P = 0.003), non-switched memory (P = 0.02), mature (P = 0.0005), resting memory (P < 0.0001) B cells, and expansion of double negative memory (P < 0.0001), activated memory (P < 0.0001) and tissue like memory (P < 0.0001) B cells were observed as compared to healthy controls. In children started on HAART, at the end of 12 months of therapy, frequencies of non-switched memory (P = 0.04), switched memory (P = 0.01), and resting memory (P = 0.003) B cells were lower; activated memory (P = 0.04), and tissue-like memory (P = 0.0001) B cells were still higher than healthy controls. HIV infection resulted in reduced memory B cells in HIV infected children. Following HAART, there was normalization of some B cell subpopulations. The study emphasizes the need of re-vaccination in HIV infected children to maintain the memory B cell pool and adequate humoral immune response against infections.

Characterization of Human CD8 T Cell Responses in Dengue Virus-Infected Patients from India.

Epidemiological studies suggest that India has the largest number of dengue virus infection cases worldwide. However, there is minimal information about the immunological responses in these patients. CD8 T cells are important in dengue, because they have been implicated in both protection and immunopathology. Here, we provide a detailed analysis of HLA-DR+ CD38+ and HLA-DR- CD38+ effector CD8 T cell subsets in dengue patients from India and Thailand. Both CD8 T cell subsets expanded and expressed markers indicative of antigen-driven proliferation, tissue homing, and cytotoxic effector functions, with the HLA-DR+ CD38+ subset being the most striking in these effector qualities. The breadth of the dengue-specific CD8 T cell response was diverse, with NS3-specific cells being the most dominant. Interestingly, only a small fraction of these activated effector CD8 T cells produced gamma interferon (IFN-γ) when stimulated with dengue virus peptide pools. Transcriptomics revealed downregulation of key molecules involved in T cell receptor (TCR) signaling. Consistent with this, the majority of these CD8 T cells remained IFN-γ unresponsive even after TCR-dependent polyclonal stimulation (anti-CD3 plus anti-CD28) but produced IFN-γ by TCR-independent polyclonal stimulation (phorbol 12-myristate 13-acetate [PMA] plus ionomycin). Thus, the vast majority of these proliferating, highly differentiated effector CD8 T cells probably acquire TCR refractoriness at the time the patient is experiencing febrile illness that leads to IFN-γ unresponsiveness. Our studies open novel avenues for understanding the mechanisms that fine-tune the balance between CD8 T cell-mediated protective versus pathological effects in dengue. IMPORTANCE: Dengue is becoming a global public health concern. Although CD8 T cells have been implicated both in protection and in the cytokine-mediated immunopathology of dengue, how the balance is maintained between these opposing functions remains unknown. We comprehensively characterized CD8 T cell subsets in dengue patients from India and Thailand and show that these cells expand massively and express phenotypes indicative of overwhelming antigenic stimulus and tissue homing/cytotoxic-effector functions but that a vast majority of them fail to produce IFN-γ in vitro Interestingly, the cells were fully capable of producing the cytokine when stimulated in a T cell receptor (TCR)-independent manner but failed to do so in TCR-dependent stimulation. These results, together with transcriptomics, revealed that the vast majority of these CD8 T cells from dengue patients become cytokine unresponsive due to TCR signaling insufficiencies. These observations open novel avenues for understanding the mechanisms that fine-tune the balance between CD8-mediated protective versus pathological effects.

Zinc Supplementation for One Year Among Children with Cystic Fibrosis Does Not Decrease Pulmonary Infection.

BACKGROUND: Children with cystic fibrosis may have a deficiency of micronutrients, including zinc, which may affect their susceptibility to infections. There is a paucity of data on zinc supplementation among children with cystic fibrosis. We hypothesized that a pharmacologic dose of zinc administered daily for 12 months would reduce the need for antibiotics by 50%. METHODS: This double-blind randomized placebo-controlled trial was conducted among children with cystic fibrosis to assess the effect of zinc supplementation on the need for antibiotics and pulmonary function tests. The children, age 5-15 y, of either sex, received either 30-mg zinc tablets or similar looking placebo tablets daily in addition to standard care. They were followed up every month for a period of 12 months and whenever they had pulmonary exacerbations. Their serum zinc was estimated at baseline and at 12 months of enrollment. During each visit, the children underwent a pulmonary function test and sputum culture. RESULTS: Of a total of 43 children screened, 40 were enrolled, and of them, 37 completed the study. The median (interquartile range) number of days of the administration of antibiotics over 12 months of follow-up among the children receiving zinc was 42 (14-97) d. In the placebo group, it was 38 (15-70) d (P = .79). There were no significant differences in the percent-of-predicted FEV1 or change in FEV1 values at 12 months (P = .44). The number of children in whose respiratory specimens Pseudomonas was isolated was similar for the 2 groups at different time intervals. The adverse events reported were similar in the 2 groups. CONCLUSION: We did not find any significant difference in the need for antibiotics, pulmonary function tests, hospitalization, colonization with Pseudomonas, or the need for antibiotics for children with cystic fibrosis receiving zinc supplementation of 30 mg/d.

Double-outlet right ventricle without interventricular communication: an unusual and challenging problem.

A ventriculoseptal defect (VSD) usually is present in patients with a double-outlet right ventricle. This report describes a case of double-outlet right ventricle with a completely shrouded inlet VSD and no interventricular shunting. This was associated with a severely regurgitant dysplastic mitral valve. The anatomy and clinical management of the patient is discussed together with an overview of the existing literature.

Corneal collagen crosslinking using riboflavin and ultraviolet-A light for keratoconus: one-year analysis using Scheimpflug imaging.

PURPOSE: To evaluate changes in corneal curvature, corneal elevation, corneal thickness, lens density, and foveal thickness after corneal collagen crosslinking with riboflavin and ultraviolet-A (UVA) light in eyes with progressive keratoconus. SETTING: Grewal Eye Institute, Chandigarh, India. METHODS: Subjective refraction, best corrected visual acuity (BCVA), Scheimpflug imaging, and optical coherence tomography were performed preoperatively and 1 week, 1, 3, and 6 months, and 1 year after crosslinking. RESULTS: There were no significant differences (P > 0.05) in mean values between preoperatively and 1 year postoperatively, respectively, in BCVA (0.22 +/- 0.10 and 0.20 +/- 0.10), spherical equivalent (-6.30 +/- 4.50 diopters (D) and -4.90 +/- 3.50 D), or cylinder vector (1.58 x 7( degrees ) +/- 3.8 D and 1.41 x 24( degrees ) +/- 3.5 D). There was no significant difference in mean measurements between preoperatively and 1 year postoperatively, respectively, for central corneal thickness (458.9 +/- 40 microm and 455.2 +/- 48.6 microm), anterior corneal curvature (50.6 +/- 7.4 D and 51.5 +/- 3.6 D), posterior corneal curvature (-7.7 +/- 1.2 D and -7.4 +/- 1.1 D), apex anterior (P = .9), posterior corneal elevation (P = .7), lens density (P = .33), or foveal thickness (175.7 +/- 35.6 microm and 146.4 +/- 8.5 microm; P = .1). CONCLUSIONS: Stable BCVA, spherical equivalent, anterior and posterior corneal curvatures, and corneal elevation 1 year after crosslinking indicate that keratoconus did not progress. Unchanged lens density and foveal thickness suggest that the lens and macula were not affected after UVA exposure during crosslinking.

Neural tube defects and herbal medicines containing lead: a possible relationship.

Neural tube defects (NTDs) are the most common cause of potentially preventable congenital malformations in the human fetus. Even with the universal folate supplementation the incidence of NTDs remain higher is developing world than the industrialized countries. We think that lead, a component of many herbal medicines taken during pregnancy for generalized well being of mother and fetus may have a role to play. Lead, a bivalent ion, competes with zinc for crossing into the gut wall and hence slowly decreases the zinc stores in the body and replaces them with lead. As zinc is required at many steps in the absorption and synthesis of biologically active folate moiety, this state of zinc deficiency leads to lack of folate in the metabolically active cells. Hence, the DNA repair and nucleic acid biosynthesis are largely affected in the rapidly dividing embryo leading to NTDs and other abnormalities. We suggest that the marketing of the herbal medicines should be regulated and scientific studies should be carried out on them in order to know their potential effects.

Square-edge polymethylmethacrylate intraocular lens design for reducing posterior capsule opacification following paediatric cataract surgery: initial experience.

PURPOSE: To compare the incidence and severity of development of posterior capsule opacification (PCO) following implantation of square-edged polymethylmethacrylate (PMMA) or hydrophobic acrylic intraocular lenses (IOLs) following paediatric cataract surgery. DESIGN: Prospective, consecutive, interventional, comparative, randomized and cross-sectional study of 40 eyes of 32 children aged between 4 and 12 years who underwent phacoemulsification and posterior chamber IOL implantation. METHODS: The patients were randomized into two groups of 20 eyes each. Group 1 eyes received a square-edge hydrophobic acrylic IOL (Acrysof SA 60 AT, Alcon Surgical, Fort Worth, Texas), and Group 2 eyes received a square-edge single-piece PMMA lens (Aurolab SQ 3600 Aurolab IOL Division, Madurai, India) in the capsular bag. No eye underwent a primary posterior capsulotomy. The PCO density was evaluated on slitlamp retroillumination photographs by using POCOman software at 3, 6, 9 and 12 months post surgery. RESULTS: The average percentage PCO on POCOman analysis was 51.23 for Group 1 and 49.49 for Group 2 (P = 0.09), and the average PCO severity grade was 1.34 in Group 1 and 1.12 in Group 2 (P = 0.08). Visual axis remained clear in 14 of 20 eyes with the acrylic lens as compared with 13 of 20 eyes with the PMMA lens. (P = 0.32). CONCLUSIONS: Square-edge PMMA IOLs offer a significant cost advantage over acrylic lenses at similar rates of PCO formation following paediatric cataract surgery, which is of significant value in developing countries.