Search

Scaphoid dislocations are an extremely rare injury. The authors herein report a 60-year-old male who was managed with open reduction and internal fixation with Kirschner wires (K-wires) and scapholunate ligament stabilisation. The aim of this case report is to comprehensively present this unusual injury along with its treatment and long-term follow-up outcome alongside a literature review to aid surgeons confronted with this rare pathology., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Rout et al.)

Generalised pustular psoriasis (GPP) is a chronic, multisystemic, autoinflammatory disease with predominantly cutaneous manifestations, characterised by recurrent episodes of widespread, macroscopic and aseptic pustules. It has a highly unpredictable, heterogeneous and unstable clinical course. There are no consensus guidelines in India for the management of GPP. The objective of this Delphi panel study was to achieve consensus on problem areas in the understanding and management of GPP. Based on the inputs from an expert panel, 19 topics across six domains were identified as being important regarding the understanding and management of GPP. Statements were developed for these 19 topics, and consensus for the statements was sought using the modified Delphi method. Twelve experts evaluated the statements, indicating their agreement or disagreement. Consensus was considered to be reached when ≥80% of experts agreed with a statement. After two rounds of discussion, consensus was reached for 17 out of 19 (89%) statements and no consensus was achieved for two (11%) statements. We have presented the statements along with the respective degrees of consensus. Wherever relevant, clarifications or additional comments by experts are provided in the document.

Acute liver failure (ALF) is usually due to viral hepatitis and toxins. We have recently seen a patient with diffuse large B-cell lymphoma (DLBCL) presenting with ALF. High clinical suspicion is necessary for making a diagnosis of this rare etiology presenting as ALF. The outcome is better if an early diagnosis is made in such cases and appropriate treatment is initiated., (© Journal of the Association of Physicians of India 2024.)

Introduction: The increasing incidence of atraumatic neck of femur (NOF) fractures, often linked to age-related bone weakening, is a notable clinical trend. This case report highlights a 72-year-old male presenting with NOF and proximal humerus fractures post-trivial fall, revealing lytic lesions suggestive of multiple myeloma (MM). Despite inconclusive skeletal and metabolic evaluations, a comprehensive surgical approach confirmed MM, emphasizing the importance of thorough diagnostic and therapeutic management in complex cases., Case Report: A 72-year-old male presented with a trivial fall resulting in hip and shoulder trauma, revealing right transcervical NOF and proximal humerus fractures on X-rays, alongside multiple lytic lesions suggesting MM. Despite inconclusive metabolic evaluations, conservative management was pursued for the humerus fracture, while a complex surgical approach involving curettage and cemented bipolar hemiarthroplasty was undertaken for the femur fracture, confirming MM on histopathology., Conclusion: Evaluating atypical MM manifestations in the appendicular skeleton requires comprehensive assessment and diagnostic procedures to influence outcomes and improve quality of life. Managing suspected pathological fractures involves detailed evaluation and surgical planning, highlighting the importance of collaboration among different specialties., Competing Interests: Conflict of Interest: Nil, (Copyright: © Indian Orthopaedic Research Group.)

Introduction: The prevalence of metabolic dysfunction-associated fatty liver disease (MAFLD) and its complication, MAFLD-related acute-on-chronic liver failure (MAFLD-ACLF), is rising. Yet, factors determining patient outcomes in MAFLD-ACLF remain understudied., Methods: Patients with MAFLD-ACLF were recruited from the Asian Pacific Association for the Study of the Liver-ACLF Research Consortium (AARC registry). The diagnosis of MAFLD-ACLF was made when the treating unit had identified the etiology of chronic liver disease as MAFLD (or previous nomenclature such as non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, or non-alcoholic steatohepatitis-cirrhosis). Patients with coexisting other etiologies of chronic liver disease (such as alcohol, hepatitis B virus, hepatitis C virus, etc.) were excluded. Data were randomly split into derivation (n = 258) and validation (n = 111) cohorts at a 70:30 ratio. The primary outcome was 90-day mortality. Only the baseline clinical, laboratory features and severity scores were considered., Results: The derivation group had 258 patients; 60% were male, with a mean age of 53. Diabetes was noted in 27% and hypertension in 29%. The dominant precipitants included viral hepatitis (hepatitis A virus and hepatitis E virus, 32%), drug-induced injury (drug-induced liver injury, 29%), and sepsis (23%). Model for End-Stage Liver Disease-Sodium (MELD-Na) and AARC scores on admission averaged 32 ± 6 and 10.4 ± 1.9. At 90 days, 51% survived. Nonviral precipitant, diabetes, bilirubin, international normalized ratio, and encephalopathy were independent factors influencing mortality. Adding diabetes and precipitant to MELD-Na and AARC scores, the novel MAFLD-MELD-Na score (+12 for diabetes, +12 for nonviral precipitant), and MAFLD-AARC score (+5 for each) were formed. These outperformed the standard scores in both cohorts., Discussion: Almost half of patients with MAFLD-ACLF die within 90 days. Diabetes and nonviral precipitants such as drug-induced liver injury and sepsis lead to adverse outcomes. The new MAFLD-MELD-Na and MAFLD-AARC scores provide reliable 90-day mortality predictions for patients with MAFLD-ACLF., (Copyright © 2024 by The American College of Gastroenterology.)

Background/aims: Patients of ulcerative colitis (UC) on follow-up are routinely evaluated by sigmoidoscopy. There is no prospective literature to support this practice. We assessed agreement between sigmoidoscopy and colonoscopy prospectively in patients with disease extent beyond the sigmoid colon., Methods: We conducted a prospective observational study at a tertiary care institute for agreement between sigmoidoscopy and colonoscopy. We assessed endoscopic activity using the Mayo Endoscopic Score (MES) and Ulcerative Colitis Endoscopic Index of Severity (UCEIS) and histological activity using the Nancy Index (NI), Robarts Histopathology Index (RHI), and Simplified Geboes Score (SGS)., Results: Sigmoidoscopy showed a strong agreement with colonoscopy for MES and UCEIS with a kappa (κ) of 0.96 and 0.94 respectively. The misclassification rate for MES and UCEIS was 3% and 5% respectively. Sigmoidoscopy showed perfect agreement (κ = 1.00) with colonoscopy for assessment of the presence of endoscopic activity in the colon using MES ≥ 1 as activity criteria and strong agreement (κ = 0.93) using MES > 1 as activity criteria. Sigmoidoscopy showed strong agreement with colonoscopy for assessment of the presence of endoscopic activity using UCEIS (κ = 0.92). Strong agreement was observed between sigmoidoscopy and colonoscopy using NI (κ = 0.86), RHI (κ = 1.00), and SGS (κ = 0.92) for the detection of histological activity. The misclassification rate for the detection of histological activity was 2%, 0%, and 1% for NI, RHI, and SGS respectively., Conclusions: Sigmoidoscopy showed strong agreement with colonoscopy for endoscopic and histologic disease activity. Sigmoidoscopy is adequate for assessment of disease activity in patients with UC during follow-up evaluation.

Introduction: Prolonged phenytoin (PHD) therapy in epileptics predisposes patients to deleterious effects on bone health causing osteoporosis; however, despite its known effect on wound healing, collagen and fibroblast proliferation, and osteogenic differentiation, its impact on fracture healing remains poorly researched, we, report two cases of early exuberant callus formation in long bone fractures in patients undergoing long-term PHD therapy., Case Report: Two female patients with known seizure disorder on long-term PHD therapy experienced proximal humerus fractures after trivial trauma. Metabolic work-up revealed low serum calcium and Vitamin D3 levels with elevated ALP, serum osteocalcin, and iPTH. Despite planned surgery, both patients showed early exuberant callus formation post-trauma, leading to conservative management with successful outcomes., Conclusion: Regular bone health monitoring is crucial for patients on long-term antiepileptic therapy, especially PHD users, to enhance treatment outcomes and address potential complications. Although the influence of PHD on fracture healing is uncertain, the cases presented hint at a potential beneficial correlation, indicating a need for more research in this domain., Competing Interests: Conflict of Interest: Nil, (Copyright: © Indian Orthopaedic Research Group.)

Introduction: Proximal radio-ulnar translocation (PRUT) with elbow dislocation, without a fracture, is an extremely unusual injury., Case: A 6-year-old female child presented to us with posterior elbow dislocation, PRUT and incomplete ulnar nerve palsy. A hematoma aspiration and reduction of the elbow joint were done with a hyper-supination manoeuvre to reverse the translocation. She was managed with an above-elbow cast for 4 weeks and showed good radiological and functional outcomes on subsequent follow-ups until 1 year., Conclusion: Early recognition of PRUT and a thorough clinico-radiological assessment are mandatory when dealing with paediatric elbow injuries. Our cadaveric study with illustrations defines the mechanism of this rare injury for better understanding., Competing Interests: The authors do not have any conflict of interests., (© 2024 The Author(s).)

Objective: Lipoid congenital adrenal hyperplasia (LCAH) is caused by mutations in STAR. A systematic review of phenotype-genotype correlation and data on testicular histology in LCAH patients is unavailable. We aim to describe our experience and provide phenotype-genotype correlation. DESIGN, PATIENTS AND MEASUREMENTS: Retrospective review of three genetically proven LCAH patients from our centre and per-patient data analysis from a systematic review of 292 probands. The phenotypic subgroups of 46,XY were Group A (typical female genitalia), Group B (atypical genitalia) and Group C (typical male genitalia)., Results: We report three new LCAH probands from India, all diagnosed post-infancy with preserved gonadal function and one novel variant. The systematic review reports 46,XY to 46,XX LCAH ratio of 1.1 (155:140). Patients with 46,XY LCAH in Group A were diagnosed in infancy (116/117) and had higher mineralocorticoid involvement than Group C (96.4% vs. 75%, p = 0.035), whereas Group C had preserved gonadal function. Hyperplastic adrenals are noted in ~60% of LCAH diagnosed with primary adrenal insufficiency in infancy. There was no report of gonadal germ cell cancer and rare reports of germ cell neoplasia in situ in adolescents, especially with intraabdominal gonads. Two-thirds of LCAH probands were East-Asian and 11/16 regional recurrent variants were from East Asia. There was minimal overlap between variants in Groups A (n = 55), B (n = 9) and C (n = 8). All nonsense and frameshift and most of the splice-site variants and deletion/insertions were present in Group A., Conclusions: We report three new cases of LCAH from India. We propose a phenotype-derived genotypic classification of reported STAR variants in 46,XY LCAH., (© 2024 John Wiley & Sons Ltd.)

There is a lack of consensus on the optimal screening strategy for insulin resistance (IR), particularly in lean women with polycystic ovary syndrome (PCOS). Therefore, we conducted a cross-sectional study in 80 women with PCOS (28 lean/52 obese) and 80 age- and body mass index (BMI)-matched controls. Using a 5-point 75-g oral glucose tolerance test (OGTT) (0, 30, 60, 90, 120 min), we examined glucose and insulin excursions, IR, insulin sensitivity, beta-cell function (ßF), and the effect of androgens on IR. Lean and obese women with PCOS had similar glucose but higher insulin (except fasting in lean women) and insulin AUC as compared to their respective controls (p < 0.05). Lean women with PCOS were equally insulin-resistant but more hyperinsulinemic than the obese controls (p < 0.05). Although ßF ([1st phase: 481.71 ± 263.53 vs. 430.56 ± 232.37], [2nd phase: 815.16 ± 447.12 vs. 752.66 ± 428.95]) was comparable in lean and obese women with PCOS, lean women had better insulin sensitivity (112.78 ± 66.26 vs. 75.49 ± 55.6) (p < 0.05). Dehydroepiandrosterone sulfate (DHEAS) and androstenedione decreased with increasing BMI in lean women, and this correlated with deteriorating insulin sensitivity and exaggerated hyperinsulinemia. In obese women with PCOS, sex hormone-binding globulin (SHBG) correlated negatively with BMI and hyperinsulinemia, and positively with insulin sensitivity. This data suggests that estimating only fasting insulin may miss IR in lean women with PCOS; hence, additional time points in OGTT will add value to screening for IR. DHEAS and androstenedione may have a beneficial effect on insulin sensitivity and may be used to screen IR in lean women, while SHBG can be used as a predictive marker for IR in obese women with PCOS., (© 2023. The Author(s), under exclusive licence to Society for Reproductive Investigation.)

Background: The revised Suicide Crisis Inventory (SCI)-2 is a self-report measure to assess the suicide crisis syndrome (SCS). We aimed to assess the factor structure, reliability, and validity of SCI-2 among adults with major depression., Methods: Using a cross-sectional design, between November 2021 and August 2022, the Hindi SCI-2, along with other self-report measures, was administered to Indian adult respondents clinically diagnosed with major depression across 24 centers in India. Confirmatory factor analysis was carried out to test the factor structure of SCI-2. Additionally, convergent, discriminant, and criterion validity were tested using bivariate or biserial correlations, as appropriate., Results: We obtained responses from 654 participants (Mean age = 36.9 ± 11.9 years, 50.2 % female). The SCI-2 fit both a one-factor (χ 2 [1769] = 14,150.74, p < .001, CFI = 0.98, RMSEA = 0.10), and five-factor solution (χ 2 [1759] = 13,130.83, p < .001,CFI = 0.98, RMSEA = 0.10) with the five-factor solution providing a significantly better fit. Internal consistencies of the SCI-2 total and subscale scores ranged from good to excellent. Most subscales significantly converged with each other and with other relevant measures although these associations were weak for thwarted belongingness and goal reengagement subscales. Small to moderate associations were noted in support of discriminant and criterion validity., Limitations: We could not assess the predictive validity of SCI-2 for suicidal behaviors., Conclusion: Consistent with prior data, the Hindi SCI-2 fit a five-factor solution and showed good psychometric properties. These findings support the use of SCI-2 to assess SCS among Indian adults with major depression., Competing Interests: Declaration of competing interest None. The authors have no conflicts to declare with regard to the contents of this manuscript., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Introduction: Maternal infections can affect the placenta, which acts as a fetomaternal barrier. This study aimed to determine the spectrum of morphologic alterations in the placentas of pregnancies complicated by SARS-CoV-2 infection and the impact on fetal or neonatal outcomes., Materials and Methods: This is a prospective case-control study. One hundred SARS-CoV-2 positive pregnant women and an equal number of SARS CoV-2 negative pregnant women in their third trimester who delivered at our tertiary care center between December 2020 and November 2021 were enrolled in the study. This study was conducted at the end of the first wave and during the second COVID-19 wave. Histopathological examination of the placentas was done using Amsterdam consensus criteria. We observed for evidence of maternal vascular malperfusion [MVM], fetal vascular malperfusion, and inflammation in the placenta., Results: The clinical findings were compared between the cases and controls. Evidence of MVM was seen in comparable numbers between the cases and controls, but as it involved less than 30% of the placental disc, it was considered an insignificant finding. Deciduitis was seen in equal proportions in both groups. The comparison between the asymptomatic and symptomatic groups failed to show any difference in placental pathology between both groups. There was no adverse fetal outcome seen in the pregnancies complicated by SARS-CoV-2 infection., Conclusion: Placental injury at the microscopic level was observed but was neither significant nor specific to the SARS-CoV-2 infection. SARS CoV-2 infection did not influence the placental pathology. Also, no adverse neonatal outcomes were observed.

Objectives: To quantitatively assess vascularity changes of acute septic hips in infants using Doppler ultrasonography. To compare these findings with asymptomatic hips, and establish a correlation for accurate diagnosis between these findings., Methods: In this prospective case-control study, we included all children under 1 year of age with a diagnosis of acute septic arthritis of the hip in the case group. For the control group, we enrolled apparently healthy, full-term neonates and infants not affected with any hip pathology. Doppler ultrasound of the medial femoral circumflex artery of the hip joint was done using a single Phillips HDI 5000 sonography machine. Following parameters were studied: peak systolic velocity (PSV), resistive index (RI), pulsatility index (PI), and systolic to diastolic ratio (SD ratio)., Results: Doppler signals and spectral waveforms were obtainable in 100% of hips in both groups. A statistically significant difference was found between the cases and controls with respect to their PSVs, RIs, PIs and SD ratios. The most striking difference was found between the PSVs of the two groups, whose mean was 6.18 in the control group and 11.8 in the case group. No significant correlation between age/gender and any of the 4 parameters was found., Conclusion: Doppler parameters are useful in raising suspicion of onset in the diagnosis of septic arthritis. No correlation was found between age or gender and any parameter in control group. These baseline values can be held valid for all children below the age of 7 months., Competing Interests: Conflict of interestThe authors declare that they have no conflict of interest., (© Indian Orthopaedics Association 2023. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Objective: To estimate incidence, risk of early and late-onset preeclampsia (PE) and understand their relationship with severity of COVID-19., Methods: Pregnant women with COVID-19 (n = 1929) were enrolled from 1 April 2020 to 24 February 2022. Primary outcome measure was incidence and risk of early onset PE in women with COVID-19., Results: The incidence of early and late-onset PE was 11.4% and 5.6%. Moderate to severe COVID-19 was associated with eight times higher risk of early onset PE [aOR = 8.13 (1.56-42.46), p  = 0.0129] compared to asymptomatic group., Conclusions: Risk of early onset PE was higher in pregnant women with symptomatic COVID-19 as compared to asymptomatic women.

Competing Interests: None

Background: Attention deficit hyperactivity disorder (ADHD) is one of the most commonly diagnosed developmental disorders and is common among referrals to child guidance clinics., Aim: This study aimed to study the impact of the lockdown during the coronavirus disease 2019 (COVID-19) pandemic on the mother's understanding of ADHD and the burden faced by her., Materials and Methods: A mixed-methods design with a combination of a qualitative and quantitative approach was adopted. An in-depth in-person semi-structured interview with the participant's mother was conducted. The qualitative and quantitative part of the study consisted of burden assessment by the Zarit Caregiver Burden Scale. The responses were transcribed, and themes were identified., Results: As far as understanding the disorder was concerned, the major themes identified were "Knew about the child's problems from teachers but online schooling made me see the child's issues in person" and "Knew about the illness but more time led to bonding and understanding the child." When questioned about the burden faced, the major themes that evolved were "Increased exhaustion taking care of a child 24/7" and "Increased burden as one felt angry and irritated with the child, the school, and the family." The Zarit caregiver questionnaire revealed a statistically significant difference in the burden of care before and after the pandemic, with a greater number of mothers falling in the mild to moderate and severe categories of burden., Conclusion: The COVID-19 pandemic increased the caregiver burden for mothers of children with ADHD. Their understanding of their child's disorder increased significantly as they could spend more time and devise different ways and means of helping their child in academics and other areas., Competing Interests: There are no conflicts of interest., (Copyright: © 2023 Industrial Psychiatry Journal.)

Background: Prediabetes is an intermediate state of hyperglycemia, which acts as a precursor to Diabetes mellitus if left untreated. Nisha (Curcuma longa) and Amalaki (Emblica officinalis) combination has been advocated as drugs of choice to treat the early manifestations of Diabetes mellitus., Objective: This prospective, randomized, single-blind, placebo-controlled, comparative study was planned to assess the efficacy and safety of Nisha-Amalaki capsules in preventing progression to Diabetes mellitus in prediabetic patients when administered for 6 months., Methods: The study was conducted on prediabetic participants randomized to receive either Nisha-Amalaki (500 mg) or placebo one capsule twice a day for six months. The effect of study medications on IDRS (Indian Diabetes Risk Score), BMI (Body Mass Index), blood sugar, serum insulin, HOMA-IR (Homeostasis Model Assessment-Estimated Insulin Resistance), HbA1c (glycated hemoglobin), oxidative markers, Ayurvedic symptoms and Quality of Life (QoL) scores was assessed at regular intervals., Results: 58 of the 62 participants enrolled completed the study. Significant fall in IDRS score [p < 0.001], BMI [p < 0.001], fasting, and 2 h post-OGTT sugar, insulin, HbA1c, HOMA-IR, and oxidative stress markers [p < 0.001] was observed in patients receiving Nisha-Amalaki at 6 months. Ayurvedic symptoms and QoL scores also improved at 6 months in the treatment group., Conclusion: Treatment with Nisha-Amalaki capsules improved all study parameters including insulin sensitivity at 6 months as compared to placebo in prediabetic patients. Thus Nisha-Amalaki should be considered as prophylactic therapy in prediabetics to delay progression to diabetes., Competing Interests: Declaration of competing interest The authors declare conflict of interest with regard to financial support received for the study., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Competing Interests: There are no conflicts of interest.

Objective: The study objective was to evaluate the prescription pattern and use of anti-seizure medications (ASMs) in patients with a seizure disorder and to evaluate if a change in the ASM dose had a beneficial effect on seizure control, observed through Therapeutic Drug Monitoring [TDM] level of ASMs., Methods: Details of anti-seizure medications with their therapeutic levels in the blood of patients with seizure disorder were analysed., Design: Hospital-based retrospective analysis of patient case records., Settings: Therapeutic Drug Monitoring OPD of a tertiary care public teaching hospital., Participants: Case records of 918 patients with seizure disorder from 2016-2021., Results: Data of men (53%) and women (47%) aged between 18-75 years was assessed About 62% (566/918) of patients were on levetiracetam, the most frequently prescribed anti-seizure medication. Whenever the ASMs dose was increased or decreased based on TDM levels, it was associated with a significant increase in the frequency of break-through seizures [OR- 5 (95% CI: 1.28-19.46)]. However, significant seizure control was observed when the patients were on the same maintenance dose of the anti-seizure medication [OR- 0.2 (95% CI: 0.06-0.63)]. Whenever an additional new anti-epileptic drug was prescribed or removed from the pre-existing anti-epileptic medications, it did not significantly impact seizure control., Conclusion: Individualising drug therapy and therapeutic drug monitoring for each patient, along with patient factors such as medication compliance, concomitant drug and disease history, and pharmacogenetic assessment, should be the ideal practice in patients with seizures for better seizure control., Funding: None declared., Competing Interests: Conflict of interest: None declared., (Copyright © The Author(s).)

Background: Chikungunya disease (CHIKD) is a threat to global health, as it impairs the quality of life of an infected individual ranging from months to years. A systematic evaluation of the serological, virological, and immunological aspects of the circulating viruses and their impact on the host response is imperative for better understanding of the evolving disease dynamics., Methods: Serum samples were collected from 196 acute CHIKD patients from ten tertiary care hospitals across India during 2016-2021. Out of 196 patients, paired convalescent samples were collected from 51 patients (one-month post-onset of symptoms). The serum samples were profiled for cytokines and neutralisation capacity. Further, chikungunya virus (CHIKV) was isolated from the acute sera and the replication kinetics of the clinical isolates was evaluated., Findings: Serological analysis indicated that neutralisation could be correlated to seroconversion in the convalescent phase but not found significant in acute phase. In the acute phase samples, there was a correlation between elevated serum levels of IFN-γ, IP-10, MCP-1 and MIG and disease severity. During convalescent phase, pro-inflammatory markers such as IL-6, IL-1β, IL-9 and IP-10 were found to be elevated with a corresponding decline in the secretion of anti-inflammatory cytokines such as IL-4 and IL-10, which correlated with persistent arthralgia. Analysis of replication of the clinical isolates revealed that 68.4% of viruses were fast-growing in the Vero cells (cytopathic effect [CPE] observed within 24 h post-infection), and their corresponding acute serum samples showed an elevated secretion of IFN-α, IL-1RA, IL-17F, IL-9, MCP-1 and MIP-1α., Interpretation: This study provides an important overview of neutralisation capabilities and cytokine responses along with virus pathogenesis associated with CHIKV infections in India., Funding: Biotechnology Industry Research Assistance Council (BIRAC)., Competing Interests: None. The current study was funded by 10.13039/501100014825Biotechnology Industry Research Assistance Council (BIRAC) (BT/NBM0101/02/18)., (© 2023 The Author(s).)

Background and Rationale: The coronavirus disease 2019 (COVID-19) pandemic has left no person unexposed to the wisdom about the need for human preparedness to tackle future pandemics irrespective of individual caste, race, religion, and education status. The extent of this change in knowledge and public perspective is difficult to measure in a populous nation like India subjected to individual freedom and cultural beliefs. Hence, we planned this study with the objective of evaluating the knowledge and perception of the Indian public towards COVID-19 disease, vaccination and research activities associated with the COVID-19 pandemic., Materials and Methods: This is an observational, single-center, cross-sectional study ( n = 244) conducted after obtaining approval from the Ethics Committee for Academic Research Projects. All consenting study participants, Indian residents aged > 18 years, were administered a prevalidated and structured questionnaire and interviewed for their honest opinion. The outcome measures were to evaluate the knowledge and perception of the study participants in each of the domains of COVID-19 disease, COVID-19 vaccination, and COVID-19-related clinical research. Demographic characteristics were summarized using descriptive statistics. All analyses were done at a 5% significance level using GraphPad InStat version 3.1. Data on the proportion of participants' responses to the questions in each of the three domains of COVID-19 disease (D), COVID-19 vaccination (V), and COVID-19-related research (R) were assessed., Results: Study participants who knew the causative agent for coronavirus disease were 93.03% (227/244), nomenclature (77.45%, 189/244), those who could define pandemic (89.34%, 218/244), preventive measures against covid (96.31%, 235/244), lungs as the most common organ affected (96.31%, 235/244) and all answered that the origin of novel coronavirus was China. The majority of them felt that COVID-19 pandemic waves would never end (39.34%, 96/244), there was no effective drug/vaccine therapy available, and the lack of oxygen/hospital beds (39%) resulted in maximum mortality, and 47.13% (115/244) were worried about future bioterrorism. The lockdown measures were justified by 161/244 (65.98%), and 93.85% supported lockdown measures to curb the spread of infection. The improvement in air quality/environment hygiene, realizing the importance of hygiene, vaccine and disease, and spending quality time with family were the best three things to happen during the pandemic, while the loss of wages, nonavailability of medicines/vaccines/oxygen/hospital beds with mental/physical health deterioration were the worst three things experienced by people. Regarding COVID-19 vaccination, the most common reason to get vaccinated was to prevent infection/critical outcomes of COVID-19 (78.27%, 191/244); 79% already suffered COVID-19 prior to vaccination, while 68.85% suffered a COVID-19 infection after taking the vaccine which was mostly asymptomatic/mild. Almost 56.96% (139/244) participants supported compulsory vaccination for all in the larger interest of society and to prevent fatal COVID-19 outcomes. There were safety concerns mainly with accelerated approval of vaccines (4.1%, 10/244) among the public, and 32.78% (80/244) attributed limited infrastructure/vaccination centers/healthcare staff as the major challenge of a mass vaccination program with 71.72% (175/244) supporting the vehicle/home vaccination drives to meet the vaccination demand in the pandemic. Approximately 38.11% (93/244) blamed the lack of sufficient vaccine manufacturing sites in India as a major vaccine shortage. Almost 82% public knew that vaccines are incapable of providing lifelong immunity or conferring protection against multiple variants, with 34.83% desiring to get polyvalent vaccines that would provide immunity against multiple COVID-19 variants. A total of 57.37% knew about clinical research, believed that the vaccine/drug development process was slow in India (29.91%), that there was a lack of funds invested in COVID-19-related clinical research (62.29%), 47.95% felt no attention was given to the alternative system of medicines, 77.86% supported accelerated drug/vaccine approval in the pandemic. Around 64.34% of the study, participants knew about the available and approved COVID-19 treatment options, such as antiviral drugs, monoclonal antibodies and vaccines. Of the total 244 study participants, 98.36% believed that clinical research is important for science to progress. When asked about their willingness to participate in COVID-19 clinical research, only 40.57% agreed, while 29% opted for non-COVID-19 related clinical research, and 29% refused to participate in any kind of clinical research. Almost 88.93% refused to take medicines without approval by drug regulatory bodies, and 54.51% agreed to participate in a controlled human challenge research study during the pandemic. The majority were of the opinion that lack of financial support (35.24%) was the main hindrance to the conduct of clinical research in India and the reason for lagging behind other countries in research and development (64.34%)., Conclusion: The survey provides insight into the public awareness and perception of the pandemic that has taught all the lessons for capacity building in automation, construction of robust medical infrastructure, and the need for future preparedness. How to cite this article: Munshi R, Maurya M. A Cross-sectional Survey of Public Knowledge and Perspective on Coronavirus Disease, Vaccination, and Related Research in India during the COVID-19 Pandemic. J Assoc Physicians India 2023;71(9):19-27., (© Journal of the Association of Physicians of India 2023.)

Background: Congenital cervicovaginal agenesis (CVA) with functioning endometrium is an extremely rare mullerian anomaly. Genital tract patency and fertility preservation are the major challenges in cases of CVA. With the advances in surgical techniques, management has shifted from a radical approach-like hysterectomy towards a more conservative approach of uterine conservation., Case Presentation and Review of the Literature: In the present study, we report our experience in managing four cases of congenital CVA with complete vaginal atresia, which were treated with a simple minimally invasive vaginal approach for UVA without using graft for neovagina creation and studied the long-term anatomic and functional result of uterovestibular anastomosis (UVA) in patients with CVA. A literature review was performed for congenital complete vaginal atresia (≤ 2 cm blind vagina), with a functioning uterus. The experience and results of this 4-year study are in accordance with the prior studies with 97% (33/34) success rate, where vestibular mucosa was used for the UVA., Conclusions: Findings of this study should encourage more gynaecologists to learn and recreate a complete vaginal approach, as no special surgical equipments are needed. Hysterectomy should only be reserved for cases, where repeated anastomosis attempts fail. This minimally invasive technique should be preferred over canalization procedures and graft, as it is associated with a higher success rate with least complications and recurrence. Conservative end-to-end anastomosis with a completely vaginal approach should be offered as the primary treatment option for CVA with total vaginal atresia., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Sexually transmitted infections (STIs) during pregnancy are associated with adverse fetal outcome. They should be aggressively sought and treated. We did an analytical study with the primary aim to know the occurrence of STIs in pregnant women and their spouses., Materials and Methods: An observational cross-sectional analytical study of pregnant women with STIs and their spouses was conducted at a tertiary care hospital. Demographic parameters and medical history were recorded. Clinical examination and necessary investigations were done in pregnant females and their spouses. History about sexual behavior and knowledge of STIs were obtained from the questionnaire., Results: The prevalence of STIs in pregnant women was 2.1% ( n = 61) out of 2894 pregnant women who attended our institute during the study period with the highest prevalence of HIV (1.1%), and out of 54 examined spouses, 32 spouses were suffering from STIs. Overall, women had poor awareness, knowledge of STIs, and preventive measures compared to men. A significant association was seen between level of education and awareness about HIV/AIDS and other STIs, both in pregnant women and their spouses., Conclusion: Our study showed an overall low prevalence of STIs among pregnant women but showed higher HIV and syphilis prevalence as compared to national prevalence. The serodiscordancy rate was found to be high in HIV, syphilis, and hepatitis B., Competing Interests: There are no conflicts of interest., (Copyright: © 2023 Indian Journal of Sexually Transmitted Diseases and AIDS.)

Objective: To evaluate and compare the clinicopathological features of giant cell tumour (GCT), central giant cell granuloma (CGCG) and peripheral giant cell granuloma (PGCG)., Material and Methods: From 2006 to 2016, all histopathologically diagnosed cases of GCT were retrieved from the Department of Pathology, T.N.M.C, Mumbai and CGCG and PGCG were retrieved from the Department of Oral Pathology, Nair Hospital Dental College, Mumbai. Statistical analysis of the clinicopathological features was done using SPSS v 21.0, IBM. Intergroup comparison of all variables was done using t test for two groups, whereas, Kruskal-Wallis test and one-way ANOVA were done for more than two groups., Results: Twelve cases of GCT, 31 cases of CGCG and 39 cases of PGCG were reported over 11 years. The mean age of occurrence for GCT, CGCG and PGCG was 30.41 years, 27.69 years and 34.03 years, respectively. GCT was seen in long bones and CGCG and PGCG showed mandible predilection. Histologically, GCT showed evenly distributed giant cells with aggregated nuclei, whereas CGCG and PGCG showed aggregated giant cells with evenly distributed nuclei. The mean value of the number of giant cells and nuclei within giant cells was maximum in GCT (27.33, 33.50) followed by CGCG (23.56, 15.51) and PGCG (21.45, 11.32)., Conclusion: The clinicopathological differences between GCT, CGCG and PGCG suggest that each one of these entities represent biologically different lesions., Supplementary Information: The online version contains supplementary material available at 10.1007/s12663-022-01724-3., Competing Interests: Conflict of interestAll the authors declare no conflict of interest related to this study., (© The Association of Oral and Maxillofacial Surgeons of India 2022.)

It is unusual to find a breast tumour in a keloid, as the management of both is distinct. In this case, a young woman was operated on 4 years ago, for a right chest wall swelling, situated near the inframammary fold. The histopathological report revealed a granuloma, for which anti-tuberculosis treatment was given. However, the swelling recurred and progressed in size over the next 3 years. Then, she consulted the dermatology department, where the swelling was managed as a keloid. There was no remission. Consequently, the possibility of a breast tumour was suspected, and the patient was referred to breast services (subdivision of the surgery department).Triple assessment of the breast lump was suggestive of a phyllodes tumour (PT). Surgical excision of the tumour was done, which showed a malignant PT. Radiotherapy was given and delayed breast reconstruction was planned., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Paratyphoid fever caused by S. Paratyphi A is endemic in parts of South Asia and Southeast Asia. The proportion of enteric fever cases caused by S. Paratyphi A has substantially increased, yet only limited data is available on the population structure and genetic diversity of this serovar. We examined the phylogenetic distribution and evolutionary trajectory of S. Paratyphi A isolates collected as part of the Indian enteric fever surveillance study "Surveillance of Enteric Fever in India (SEFI)." In the study period (2017-2020), S. Paratyphi A comprised 17.6% (441/2503) of total enteric fever cases in India, with the isolates highly susceptible to all the major antibiotics used for treatment except fluoroquinolones. Phylogenetic analysis clustered the global S. Paratyphi A collection into seven lineages (A-G), and the present study isolates were distributed in lineages A, C and F. Our analysis highlights that the genome degradation events and gene acquisitions or losses are key molecular events in the evolution of new S. Paratyphi A lineages/sub-lineages. A total of 10 hypothetically disrupted coding sequences (HDCS) or pseudogenes-forming mutations possibly associated with the emergence of lineages were identified. The pan-genome analysis identified the insertion of P2/PSP3 phage and acquisition of IncX1 plasmid during the selection in 2.3.2/2.3.3 and 1.2.2 genotypes, respectively. We have identified six characteristic missense mutations associated with lipopolysaccharide (LPS) biosynthesis genes of S. Paratyphi A, however, these mutations confer only a low structural impact and possibly have minimal impact on vaccine effectiveness. Since S. Paratyphi A is human-restricted, high levels of genetic drift are not expected unless these bacteria transmit to naive hosts. However, public-health investigation and monitoring by means of genomic surveillance would be constantly needed to avoid S. Paratyphi A serovar becoming a public health threat similar to the S. Typhi of today., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Jacob et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Acne vulgaris is a skin condition characterized by the inflammation or hyperactivity of sebaceous glands on the skin, which results in the creation of comedones, lesions, nodules, and perifollicular hyperkeratinization. Increased sebum production, follicular blockage, and bacterial colonization may contribute to the disease etiology. Environmental factors, hormonal imbalance, and genetic predisposition can alter the severity of the disease. Its mental and monetary effects can be problematic for the society. In this study, we examined the role of isotretinoin in the treatment of acne vulgaris based on evidence from prior research. This review literature study compiled publications on the treatment of acne vulgaris from 1985 to 2022 based on PubMed and Google Scholar publications. Additional bioinformatics analyses were accompanied by GeneCards, STRING model, and DrugBank databases. These complementary analyses were designed to obtain a better perspective of personalized medicine which is highly required for dose-precise administrations of acne vulgaris treatment. Isotretinoin has been recognized as an effective treatment for acne vulgaris, particularly in cases that have been resistant to previous medications or have resulted in scarring, according to gathered data. Oral isotretinoin inhibits the proliferation of Propionibacterium acne, a critical factor in the development of acne lesions; also, it has been shown to be effective in reducing the number of Propionibacterium-resistant patients and regulating sebum production and reducing sebaceous gland size more effectively than other treatment options resulting in general improvements in skin clarity and acne severity and reduce inflammatory in 90% of patients. In addition to its efficacy, the majority of patients have shown that oral isotretinoin is well tolerated. This review highlights the use of oral retinoids, particularly isotretinoin, as an effective and well-tolerated treatment option for acne vulgaris. It has been proven that oral isotretinoin is useful for achieving long-lasting remission in patients with severe or resistant instances. Despite the fact that oral isotretinoin is related to a number of potential harmful effects, skin dryness was the most common side effect reported by patients that can be managed with the aid of suitable monitoring and drug administration against specific genes identified by genotyping of the susceptible variants of genes involved in TGFβ signaling pathway., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Scott-Emuakpor et al.)

1. To study the various clinical presentations, microbiological and radiological profiles in patients of skull base osteomyelitis, to know about the underlying comorbidities or immunocompromised status and its relation to the disease and its management. 2. To study the effect of long term intravenous antimicrobial therapy with respect to clinical outcomes and radiological improvement and to study the long term outcomes of the treatment. This is an observational prospective and retrospective study. Thirty adult patients who were diagnosed with skull base osteomyelitis by clinical/microbiological and or radiological features were treated with long term intravenous antibiotics according to pus culture and s for 6-8 weeks and they were followed up for 6 months. Clinical improvement in symptoms and signs, radiological imaging features and pain score were assessed after 3 and 6 months. We noticed in our study that skull base osteomyelitis are more common in older patients with male predominance. Presenting symptoms include ear discharge, otalgia, hearing, cranial nerve palsy. Immunocompromised state, mainly Diabetes mellitus is closely associated with skull base osteomyelitis. Majority of patients showed Pseudomonas related species on pus culture and sensitivity. All the patients showed temporal bone involvement in CT and MRI. Other bones involved were shenoid, clivus and occipital bone. Majority showed good clinical response to intravenous ceftazidime, combination of piperacillin and tazobactum, followed by combination of piptaz and Ciprofloxacin. Treatment duration was 6-8 weeks. All patients showed clinical improvement in symptoms and relief in pain after 3 and 6 months. Skull base osteomyelitis is a rare condition, most commonly seen in elderly patients with diabetes mellitus and or other immunocompromised condition. Pseudomonas related species are the major causes of skull base osteomyelitis. Long term pus culture and sensitivity bases intravenous antibiotic therapy is the main stay of treatment., (© Association of Otolaryngologists of India 2023, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Objectives: To develop and validate a modified HPLC-UV method for the estimation of serum levetiracetam levels and to assess the usefulness of serum levetiracetam estimation in epileptic patients., Materials and Methods: Modification of a previously existing HPLC-UV method was performed using liquid- liquid phase extraction and processing using reverse phase analytic HPLC-UV detector technique followed by method validation. Serum samples of patients attending our hospital's Therapeutic Drug Monitoring Outpatient Department services were analyzed for levetiracetam levels using the study method. Data of the past 6 years (2015-2020) were descriptively analyzed., Results: The modified HPLC-UV method was validated as per ICH Q2 (R1) 2005 guidelines. Usefulness of levetiracetam estimation was assessed in 1383 patients (635 children, 683 adults, 40 elderly, and 25 pregnant women). Levetiracetam levels were within the therapeutic range (TR) in 520 children, 543 young adults, 35 elderly patients, and nine pregnant women. In 112 of 232 patients with low levetiracetam levels, poor compliance was elicited. Of 641 patients on polytherapy, 446 patients had levetiracetam values within TR, whereas 29 had values above and 166 patients had values less than TR. Sodium valproate, phenytoin sodium, and carbamazepine affected levetiracetam levels when given concomitantly. Levetiracetam dose was adjusted in 61 patients with abnormal levels for better clinical response. Good seizure control was noted in 913 (82.47%) patients whose levels were within TR, whereas 136 (58.62%) patients with low levels reported an increase in seizure frequency., Conclusions: The modified HPLC-UV method is simple, rapid, efficient, and reliable for assaying serum levetiracetam., Competing Interests: None

Background: Acute kidney injury (AKI) occurs in 20-50% of patients with cirrhosis and is associated with a poor prognosis. The aim of the study is to identify the baseline factors affecting mortality in these patients at 30 and 90 days. Methods: We enrolled 117 patients with cirrhosis and AKI and followed them up prospectively. Results: Distribution of International club of ascites AKI stages was: 26 (22.03%) stage 1, 59 (50%) stage 2, and 33 (28%) stage 3. Mortalities at 30 and 90 days were 27 (22.8%) and 33 (27.9%) respectively. On multivariate analysis, variables affecting mortality at 30 days were serum creatinine level>2 mg% at 48 hours after AKI development (adjusted OR 7.93, P =0.02) and leukocytosis (total leucocyte count>11000/mm 3 ) at admission (adjusted OR 6.54, P =0.002). Only leukocytosis at admission was a predictor of 90 days mortality (adjusted OR 4.76, P =0.01). Though not statistically significant, patients not responding to standard medical treatment had 3 times higher mortality at 30 days, while the maximum AKI stages (2 and 3) had eight times higher mortality at 90 days. Conclusion: In cirrhosis, AKI increases short-term mortality. High serum creatinine at 48 hours affects mortality at 30 days, while leukocytosis at baseline predicts mortality at 30 and 90 days. Progression to a higher AKI stage impacts prognosis., Competing Interests: Competing Interests The authors declare no conflict of interest related to this work., (© 2023 Middle East Journal of Digestive Diseases.)

Context: It is postulated that 25(OH)D deficiency is associated with a worse prognosis of COVID-19., Aims: We aimed to find out whether baseline serum 25-hydroxy vitamin D levels were correlated with COVID-19 disease severity or not in Indian population., Settings and Design: It is a prospective observational study., Methods and Material: We prospectively recruited 200 COVID-19-positive adult patients and measured their baseline vitamin D levels on admission and prospectively followed their clinical course for their outcome and correlated the association., Statistical Analysis Used: The continuous data were represented as mean (±SD) or median (IQR), while the categorical data were represented as proportions. Parametric data were analysed using unpaired T -test and ANOVA for two and more than two groups, and for categorical, nonparametric data, Chi-square test were applied. A two-sided P value of <0.05 was considered as statistically significant with 95% confidence interval., Results: Eighty-six per cent (172/200) of patients had hypovitaminosis D (<30 ng/mL). The prevalence of 25(OH) severe deficiency, deficiency and vitamin D insufficiency was 23%, 41% and 22%, respectively. Clinical severity was graded as asymptomatic (11%), mild (14%), moderate (14.5%), severe (37.5%) and critical (22%). Sixty per cent of patients had clinically severe or critical disease requiring oxygen support with eleven per cent ( n = 22) mortality overall. Age ( P : 0.001), HTN ( P : 0.049) and DM ( P : 0.018) were negatively associated with clinical severity. No linear association was found between vitamin D levels and clinical severity. Low vitamin D levels had a significant inverse association with inflammatory markers like neutrophil-lymphocyte ratio (NLR, P : 0.012) and IL-6 ( P : 0.002)., Conclusions: Vitamin D deficiency was not associated with worse outcomes of COVID-19 infection in Indian population., Competing Interests: There are no conflicts of interest., (Copyright: © 2023 Indian Journal of Endocrinology and Metabolism.)

Competing Interests: There are no conflicts of interest.

This retrospective observational study was aimed at defining the demographic and clinical characteristics as well as severity profile of COVID-19 disease in children admitted to dedicated COVID-19 tertiary care hospital in Mumbai, India, during the second wave. COVID-19 infection detected in children (1 month-12 years) by the rapid antigen test or reverse transcriptase polymerase chain reaction or TRUENAT from March 1 to July 31, 2021 on throat/nasopharyngeal samples were enrolled and their clinical features and outcomes were studied. During the study period, 77 children with COVID-19 infection were admitted, of whom two-third (59.7%) were <5 yr old. The common presenting symptom was fever (77%), followed by respiratory distress. Comorbidities were noted in 34 (44.2%) children. Most of the patients belonged to the mild severity category (41.55%). While 25.97 per cent of patients presented in severe category and 19.48 per cent were asymptomatic. Admission to intensive care was needed in 20 (25.9%) patients, with 13 patients needing invasive ventilation. Nine patients succumbed while 68 were discharged. The results might help understand the course, severity profile and outcomes of the second wave of the COVID-19 pandemic in the paediatric population.

Melanocortins are tiny protein molecules formed by the post-translational cleavage of proopiomelanocortin. These are bioactive peptides that are responsible for human and lower animal pigmentation patterns, energy homeostasis, and sexual function modulation. These peptides regulate numerous physiological functions by being generated in the central nervous system and peripheral tissues. Melanocortins elicit their varied biological effects by binding to a separate family of G protein, two primary proteolytic enzymes, proconvertases 1 and 2, according to recent research. These breakthroughs have opened up new avenues for research into the role of melanocortins, antagonists, and receptors in a number of physiological activities., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Objective: To study clinical presentation, disease severity, pregnancy complications, and maternal outcomes in women affected with coronavirus disease 2019 (COVID-19) during the third wave compared with the first and second waves of COVID-19., Methods: A retrospective, observational cohort study was conducted among 2058 pregnant and postpartum women with COVID-19 admitted during three wave periods at a tertiary care COVID-19-dedicated hospital., Results: The number of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) -infected pregnant and postpartum women with symptoms of COVID-19 was four times higher during the third wave compared with the first (odds ratio [OR] 4.6, 95% confidence interval [CI] 3.5-6.0, P < 0.001). There was a significantly lower proportion of pregnant and postpartum women with moderate to severe COVID-19 during the third wave (0.6%, 2/318) compared with those during the first wave (2.4%, 27/1143, P < 0.001) and second wave (14.4%, 86/597, P < 0.001). The intensive care/high dependency unit admissions during the third wave were significantly lower (2.5%, 8/318) than during the second wave (14.7%, 88/597; OR 0.2, 95% CI 0.1-0.3, P < 0.001) but similar to the first wave (2.4%, 27/1143)., Conclusions: Decreased severity of COVID-19, reduced maternal mortality, and morbidity were reported in the third wave compared with the first wave and second wave of COVID-19 in the Mumbai Metropolitan Region, India., Trial Registration: The study is registered with the Clinical Trial Registry of India (Registration no: CTRI/2020/05/025423)., (© 2022 International Federation of Gynecology and Obstetrics.)

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) that was first identified in December 2019, in Wuhan, China was found to be the etiological agent for a novel respiratory infection that led to a Coronavirus Induced Disease named COVID-19. The disease spread to pandemic magnitudes within a few weeks and since then we have been dealing with several waves across the world, due to the emergence of variants and novel mutations in this RNA virus. A direct outcome of these variants apart from the spike of cases is the diverse disease presentation and difficulty in employing effective diagnostic tools apart from confusing disease outcomes. Transmissibility rates of the variants, host response, and virus evolution are some of the features found to impact COVID-19 disease management. In this review, we will discuss the emerging variants of SARS-CoV-2, notable mutations in the viral genome, the possible impact of these mutations on detection, disease presentation, and management as well as the recent findings in the mechanisms that underlie virus-host interaction. Our aim is to invigorate a scientific debate on how pathogenic potential of the new pandemic viral strains contributes toward development in the field of virology in general and COVID-19 disease in particular., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Mahilkar, Agrawal, Chaudhary, Parikh, Sonkar, Verma, Chitalia, Mehta, Koner, Vijay, Shastri and Sunil.)

Competing Interests: The authors have no conflicts of interest to declare.