Treatment challenges in the management of difficult-to-treat gram-positive infections: A consensus view apropos therapeutic role of novel anti-MRSA antibiotics, levonadifloxacin (IV) and alalevonadifloxacin (oral).

PURPOSE: Treatment of antibiotic-resistant Gram-positive infections (GPIs), including methicillin-resistant Staphylococcus aureus (MRSA) is becoming increasingly difficult, particularly in patients with multiple co-morbidities who require antibiotics with greater safety and a consistent pharmacokinetic/pharmacodynamic (PK/PD) profile. Such difficult-to-treat GPIs are often associated with poor outcomes, extended hospital stay and increased expenditure. This can be partly attributed to the limited safety and aberrant PK/PD profile of existing anti-MRSA antibiotics. In this context, intravenous levonadifloxacin and its oral prodrug alalevonadifloxacin are novel anti-MRSA antibiotics that have significant advantages over conventional anti-Gram-positive antibiotics. The purpose of this paper was to generate a consensus on the optimal use of levonadifloxacin and alalevonadifloxacin for tackling resistant Gram-positive infections in patients with multiple co-morbidities. METHOD: Using a modified Delphi approach that combines critical appraisal of evidence and expert opinion, therapeutic use of levonadifloxacin and alalevonadifloxacin in various clinical scenarios and specific unmet conditions was deliberated. Fifteen expert members from medicine, critical-care, emergency, microbiology, and intensive-care disciplines participated and voted on 11 pre-conceived statements. When there was at least 70 % agreement, a consensus was reached. RESULTS: Following the voting, agreements were reached on 10 out of the 11 statements. Broadly, a consensus was reached in defining the therapeutic role of levonadifloxacin and alalevonadifloxacin in the treatment of various clinical indications involving resistant Gram-positive pathogens, including MRSA, in patients with co-morbidities, such as co-existing or increased risk for kidney dysfunction or hepatic disease and/or immunosuppression; also, in therapeutically challenging conditions caused by Gram-positive bacteria such as bacteraemia, bone and joint infection, diabetic foot infection, febrile neutropenia, and hospital-acquired pneumonia. CONCLUSIONS: This consensus supports the therapeutic use of levonadifloxacin and alalevonadifloxacin in the treatment of antibiotic-resistant GPIs, including those caused by MRSA and certain polymicrobial infections, in patients with multiple co-morbidities requiring drug with adequate safety and consistent efficacy.

Pediatric Ectopic Cushing Syndrome Caused by Hepatic Neoplasms: A Case Report and Systematic Review.

Ectopic adrenocorticotropic hormone (ACTH) syndrome (EAS) is rare in children, and localizing the source of EAS is often challenging. Here, we report EAS in an adolescent boy who presented with Cushingoid features and had endogenous ACTH-dependent hypercortisolism on hormonal evaluation. Abdominal ultrasound and CT revealed a hepatic lesion with characteristics suggestive of hemangioma, whereas the lesion was tracer non-avid on 68Ga-DOTANOC positron emission tomography/CT. A regional sampling of ACTH was done to confirm the hepatic lesion as the source of EAS, and a definitive ACTH gradient was observed between the hepatic vein and the right internal jugular vein. Further, a preoperative biopsy of the lesion revealed a small round cell tumor with positive immunostaining for ACTH and synaptophysin, suggestive of a neuroendocrine tumor. The patient was managed with partial hepatectomy, resulting in hormonal and clinical remission of Cushing syndrome. In a systematic review of pediatric EAS due to primary hepatic tumors (n = 11), calcifying nested stromal epithelial cell tumors were the most common. EAS-associated hepatic tumors were larger (≥10 cm) except benign primary hepatic neuroendocrine tumors (PHNET). The latter were misdiagnosed as hemangioma in two cases by anatomical imaging but correctly diagnosed by somatostatin receptor scintigraphy. Hepatic tumors causing EAS in children required extensive resection, except benign PHNET. Nevertheless, all benign tumors with an uncomplicated perioperative course demonstrated disease-free survival over a median follow-up period of two years.

Functional and clinical outcome with modified lateral approach total hip arthroplasty in stiff hips with ankylosing spondylitis.

BACKGROUND: Ankylosing spondylitis at total hip arthroplasty (THA) has significant hip stiffness with flexion deformity, restricted mobility, and function. Range of movement (ROM) improvement with good functional outcome is seen following THA in these hips. The modified Hardinge approach without abductor compromise is helpful in these stiff hips with associated flexion deformity. AIM: To assess improvement in ROM and functional outcomes with a modified lateral approach THA in ankylosing spondylitis with stiff hips. METHODS: A total of 69 hips that underwent THA with a modified Hardinge approach in 40 patients were evaluated at a mean follow-up of 38.33 mo. All individuals ambulated with weight-bearing as tolerated and ROM exercises from the 1st postoperative day. Modified Harris hip score and ROM were assessed during follow-up. Quality of life assessments using the 36-item and 12-item short form health surveys were done along with clinical and functional outcomes at follow-up. SPSS 22.0 was used for statistical analysis. The correlation of ROM and functional score change was performed using Pearson's correlation coefficient. RESULTS: Sixty-nine hips with a significant decrease in ROM preoperatively with 32 clinically fused hips showed significant improvement in flexion range. The mean flexion in 69 hips improved from 29.35 ± 31.38 degrees to 102.17 ± 10.48 degrees. The mean difference of 72.82 with a P value < 0.0001 was significant. In total, 45 out of 69 hips had flexion deformity, with 13 hips having a deformity above 30 degrees. The flexion during the follow-up was below 90 degrees in 3 hips. Eleven hips had flexion of 90 degrees at follow-up, while the remaining 55 hips had flexion above 100 degrees. Modified Harris hip score improved from 17.03 ± 6.02 to 90.66 ± 7.23 (P value < 0.0001). The 36-item short form health survey at the follow-up indicated health status in 40 patients as excellent in 11, very good in 20, good in 5, fair in 3, and poor in 1. The mean mental health score was 84.10 ± 11.58. Pain relief was good in all 69 hips. Altogether, 28/40 patients (70%) had no pain, 9 patients (22%) had occasional pain, and 3 patients (8%) had mild to moderate pain with unusual activity. Heterotopic ossification was seen in 21 hips with Brooker class 1 in 14 hips. CONCLUSION: Modified Hardinge approach THA in ankylosing spondylitis with stiff hips with flexion deformity significantly improved ROM, Harris hip score, and quality of life indicated by the 36-item and 12-item short form health surveys.

Evaluation of the Safety and Efficacy of Favipiravir in Adult Indian Patients with Mild-to-Moderate COVID-19 in a Real-World Setting.

Purpose: To evaluate the safety and efficacy of favipiravir, which is prescribed for the treatment of patients with mild-to-moderate coronavirus disease 2019 (COVID-19) in India. Patients and Methods: This was a prospective, open-label, multicenter, single-arm postmarketing study conducted in India. Patients with mild-to-moderate COVID-19 received favipiravir (3600 mg [1800 mg orally twice daily] on the first day, followed by 800 mg orally twice daily, up to a maximum of 14 days) as a part of their treatment. The primary endpoints were to evaluate the safety of favipiravir by assessing the number of adverse events (AEs) and treatment-related AEs. The secondary endpoints were to evaluate the efficacy of favipiravir by assessing time to clinical cure, rate of clinical cure, time to pyrexia resolution, rate of oxygen requirement, and all-cause mortality. Results: A total of 1083 patients were enrolled in this study from December 2020 to June 2021. Adverse events were reported in 129 patients (11.9%), 116 (10.7%) of whom had mild AEs. Dose modification or withdrawal of favipiravir treatment was reported in four patients (0.37%). The median time to clinical cure and pyrexia resolution was 7 and 4 days, respectively. A total of 1036 patients (95.8%) exhibited clinical cure by day 14. Oxygen support was required by 15 patients (1.4%). One death was reported, which was unrelated to favipiravir. Conclusion: In the real-world setting, favipiravir was well-tolerated, and no new safety signals were detected.

Forward Model and Deep Learning Based Iterative Deconvolution for Robust Dynamic CT Perfusion.

Perfusion maps obtained from low-dose computed tomography (CT) data suffer from poor signal to noise ratio. To enhance the quality of the perfusion maps, several works rely on denoising the low-dose CT (LD-CT) images followed by conventional regularized deconvolution. Recent works employ deep neural networks (DNN) for learning a direct mapping between the noisy and the clean perfusion maps ignoring the convolution-based forward model. DNN-based methods are not robust to practical variations in the data that are seen in real-world applications such as stroke. In this work, we propose an iterative framework that combines the perfusion forward model with a DNN-based regularizer to obtain perfusion maps directly from the LD-CT dynamic data. To improve the robustness of the DNN, we leverage the anatomical information from the contrast-enhanced LD-CT images to learn the mapping between low-dose and standard-dose perfusion maps. Through empirical experiments, we show that our model is robust both qualitatively and quantitatively to practical perturbations in the data.

Anatomical Landmark Detection using Deep Appearance-Context Network.

Accurate identification of anatomical landmarks is a crucial step in medical image analysis. While deep neural networks have shown impressive performance on computer vision tasks, they rely on a large amount of data, which is often not available. In this work, we propose an attention-driven end-to-end deep learning architecture, which learns the local appearance and global context separately that helps in stable training under limited data. The experiments conducted demonstrate the effectiveness of the proposed approach with impressive results in localizing landmarks when evaluated on cephalometric and spine X-ray image data. The predicted landmarks are further utilized in biomedical applications to demonstrate the impact.

Short term follow-up of patients presenting with acute onset diabetes and diabetic ketoacidosis during an episode of COVID-19.

BACKGROUND AND AIMS: Acute onset diabetes and diabetic ketoacidosis (DKA) can be precipitated by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection in individuals with no history of diabetes. However, data regarding the follow-up of these individuals are scarce. METHODS: Three patients (data of two patients already published) with acute onset diabetes and DKA, precipitated by coronavirus disease 2019 (COVID-19), were followed for 14 weeks to assess the behavior of the diabetes. Detailed history, anthropometry, laboratory investigations, imaging studies, clinical course and outcomes were documented. RESULTS: Three individuals developed symptoms suggestive of SARS CoV-2 infection. After a few days, they were detected to have COVID-19 pneumonia, based on reverse transcription-polymerase chain reaction (RT-PCR) assay and chest imaging. In the meantime, they also developed acute onset diabetes and DKA, which were precipitated by COVID-19. They responded well to treatment, including intravenous fluids and insulin. After around one week, they were transitioned to multiple shots of subcutaneous insulin. After about 4-6 weeks, their insulin requirement diminished and oral antihyperglycemic drugs were initiated. At the last follow-up (14 months), they had controlled glycemia with oral antihyperglycemic medicines. CONCLUSIONS: COVID-19 can induce acute onset diabetes and DKA in some individuals with no history of diabetes. These features resemble type 1 diabetes. However, after 4-6 weeks, their requirement for exogenous insulin diminishes and respond to oral antihyperglycemic medications. Long term follow up is required to further understand the type of diabetes induced by SARS CoV-2 infection in these individuals.

Diabetic ketoacidosis precipitated by COVID-19: A report of two cases and review of literature.

BACKGROUND AND AIMS: The relationship between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease (COVID-19) and diabetes mellitus is bidirectional. On one hand, diabetes mellitus is associated with an increased risk of severe COVID-19. On the other hand, new onset diabetes and severe metabolic complications of pre-existing diabetes, including diabetic ketoacidosis (DKA) have been observed in patients with COVID-19. In this report, we describe two patient with diabetes mellitus who presented to our hospital with DKA. We also reviewed almost all published cases of DKA that had been precipitated by COVID-19. METHODS: Two patients were admitted with DKA, who were diagnosed to have COVID-19 on the basis of real time reverse transcription-polymerase chain reaction (RT-PCR) assay. Detailed history, anthropometry, laboratory investigations, imaging studies, clinical course and management outcomes were documented. RESULTS: First patient (30-year-male) had undiagnosed diabetes and no other comorbidities, and COVID-19 precipitated DKA. He also had COVID-19-associated pneumonia. Second patient (60-year-male) had long duration hypertension with no prior history of diabetes and developed cerebrovascular accident (CVA). He was also diagnosed with COVID-19 (RT-PCR assay) and DKA in the hospital. CVA and COVID-19 could have precipitated DKA. Both patients responded well to treatment and were discharged in a stable condition. CONCLUSIONS: These cases show that COVID-19 can precipitate DKA in a significant number of patients. DKA can occur in patients with pre-existing diabetes or newly diagnosed diabetes. As COVID-19 and diabetes are prevalent conditions, high degree of suspicion is required to diagnose DKA timely in order to improve the prognosis of COVID-19-related diabetic ketoacidosis.

Structural insights of JAK2 inhibitors: pharmacophore modeling and ligand-based 3D-QSAR studies of pyrido-indole derivatives.

In this study we have performed pharmacophore modeling and built a 3D QSAR model for pyrido-indole derivatives as Janus Kinase 2 inhibitors. An efficient pharmacophore has been identified from a data set of 51 molecules and the identified pharmacophore hypothesis consisted of one hydrogen bond acceptor, two hydrogen bond donors and three aromatic rings, i.e. ADDRRR. A powerful 3D-QSAR model has also been constructed by employing Partial Least Square regression analysis with a regression coefficient of 0.97 (R(2)) and Q(2) of 0.95, and Pearson-R of 0.98.