Eosinophilic granuloma of the cervical spine in a young adult: A rare case report.

Background: Spinal eosinophilic granulomas (EG) are rare tumors, mostly reported in the pediatric age group. They constitute <1% of primary bone neoplasms, and cervical spine involvement is uncommon. Case Description: A 20-year-old male presented with neck pain for a 4-month duration. Six years previously, he had received six cycles of vinblastine for biopsy-proven histiocytosis of an axillary lymph node; this resulted in incomplete remission. Present magnetic resonance/computed tomography (CT) imaging revealed a lytic C2 body lesion with atlantoaxial instability. When the CT-guided biopsy was suggestive of EG, he was managed with definitive surgery and adjuvant radiotherapy. Conclusion: Cervical spine EG is rare in adults. CT-guided biopsy should confirm the diagnosis and should be followed by definitive surgery and adjuvant radiotherapy.

Relative bioavailability of fedratinib through various alternative oral administration methods in healthy adults.

Fedratinib is an oral Janus kinase 2-selective inhibitor for the treatment of adult patients with intermediate-2 or high-risk myelofibrosis; however, some patients have difficulty with oral dosing. This randomized, phase 1, open-label, 2-part crossover study evaluated the relative bioavailability, safety, tolerability, taste, and palatability of fedratinib resulting from various alternative oral administration methods in healthy adults. Participants could receive fedratinib 400 mg orally as intact capsules along with a nutritional supplement; as contents of capsules dispersed in a nutritional supplement, delivered via nasogastric tube; or as a divided dose of 200 mg orally twice daily as intact capsules with a nutritional supplement. Fifty-eight participants received treatment. Total exposure to fedratinib was similar after oral administration of intact capsules or when dispersed in a nutritional supplement (area under the plasma concentration-time curve from time 0 to the time of the last quantifiable concentration geometric mean ratio [AUC0-t GMR] [90% CI], 1.007 [0.929-1.092]). Total exposure to fedratinib was slightly reduced following nasogastric administration (AUC0-t GMR 0.850 [0.802-0.901]) and as a divided dose (AUC0-t GMR 0.836 [0.789-0.886]). No new safety signals were identified for fedratinib, and most participants found the taste and palatability acceptable when dispersed in a nutritional supplement. Overall, results suggest no clinically meaningful differences in total exposure to fedratinib between the tested oral administration methods. These findings may facilitate administration of fedratinib to patients who are intolerant of swallowing the capsule dosage form. (ClinicalTrials.gov: NCT05051553).

Vulvar Leiomyoma Masquerading as Bartholin Cyst: A Case Report of Unveiled Diagnosis and Surgical Management.

Vulvar leiomyomas are rare benign tumors originating from smooth muscle cells of the vulvar tissue. We present the case of a 44-year-old female patient complaining of a painless vulval mass for 12 years, gradually increasing from 1x1 cm to 5x4 cm. Clinical assessment initially suggested a Bartholin cyst because of its non-tender and non-fluctuant nature. However, surgical intervention revealed an unexpected diagnosis of vulvar leiomyoma, measuring 5x5x4 cm. The patient underwent successful excision and repair under spinal anesthesia. This case underscores the significance of meticulous clinical evaluation and accurate histopathological examination in distinguishing vulvar masses. Accurate diagnosis guides appropriate management, and long-term follow-up prevents complications and recurrence. This report highlights the diagnostic challenges of rare vulvar lesions and the importance of a comprehensive approach to their evaluation and treatment.

Prevalence and associated factors of diabetic retinopathy among people with diabetes screened using fundus photography at a community diabetic retinopathy screening program in Nepal.

BACKGROUND: This study aimed to assess the prevalence and associated factors of diabetic retinopathy (DR) and vision threatening DR (VTDR) among people with diabetes screened using fundus photography in Nepal. METHODS: This is a retrospective study among people with diabetes presented for DR screening using fundus photography from 2013 to 2019. Detailed demographics, duration of diabetes, medical history, visual acuity, and grading of DR on fundus photography were analyzed. Fundus camera used in the study were;Topcon digital fundus camera 900 CXR and digital portable fundus cameras (Nidek-10 portable non-mydriatric fundus camera; Versacam & Trade & Alpha, France), and a Zeiss portable fundus camera (Zeiss Visucout 100). Macula centred and disc centred 45 degree two images were taken from each eye. Pupil were dilated in cases where there was media haze in un-dilated cases. DR was graded using early treatment diabetic retinopathy study criteria. The images were graded by fellowship trained retina specialist. DR prevalence included any DR changes in one or both eyes. RESULTS: Total of 25,196 patients with diabetes were enrolled. Mean age was 54.2 years with Standard Deviation (S.D):12.9 years, ranging from 6 years to 97 years. Type 1 and type 2 diabetes comprised of 451 people (1.79%) and 24,747 (98.21%) respectively. Overall, 1.8% of the images were un-gradable. DR prevalence was 19.3% (95% Confidence Interval (CI): 18.8 - 19.7%). DR prevalence in type 1 and type 2 diabetes was 15.5% (95% CI: 12.5 - 18.6%) and 19.3% (CI: 18.8 - 19.8%) respectively. Clinically significant macular edema (CSME) was found in 5.9% (95% CI: 5.6-6.2%) and VTDR in 7.9% (95% CI: 7.7-8.3%). In multivariate analysis, our study revealed strong evidence to suggest that there is meaningful association between DR and VTDR with duration of diabetes, diabetic foot, diabetic neuropathy, agriculture occupation, those under oral hypoglycaemic agents or insulin or both as compared to those under diet only, and presenting visual acuity > 0.3LogMAR. CONCLUSION: Prevalence and associated factors for DR and VTDR were similar to other DR screening programs in the region. Emphasis on wider coverage of DR screening could help for timely detection and treatment of STDR to avoid irreversible blindness.

A survey on recent trends in deep learning for nucleus segmentation from histopathology images.

Nucleus segmentation is an imperative step in the qualitative study of imaging datasets, considered as an intricate task in histopathology image analysis. Segmenting a nucleus is an important part of diagnosing, staging, and grading cancer, but overlapping regions make it hard to separate and tell apart independent nuclei. Deep Learning is swiftly paving its way in the arena of nucleus segmentation, attracting quite a few researchers with its numerous published research articles indicating its efficacy in the field. This paper presents a systematic survey on nucleus segmentation using deep learning in the last five years (2017-2021), highlighting various segmentation models (U-Net, SCPP-Net, Sharp U-Net, and LiverNet) and exploring their similarities, strengths, datasets utilized, and unfolding research areas.

Timing of Surgery for Ruptured Arteriovenous Malformations with Intracerebral Hemorrhage: A Systematic Review and Meta-Analysis.

Background: Both early surgery and delayed surgery of ruptured arteriovenous malformation (AVM) with intracerebral hemorrhages have their own advantages and disadvantages. Due to lack of large case-control studies, timing of surgery for ruptured AVM excision is still a controversial topic. So, we did a systemic review and meta-analysis, including our experience of early surgery, to see which surgical strategy has a favorable outcome. Materials and Methods: We systematically searched several databases and journals to screen eligible studies. After synthesizing data, results of individual studies of early and delayed surgery were calculated as the effect size (ES) and 95% confident intervals (CIs), and the pooled ES was calculated using random-effects model. Heterogeneity and publication bias were assessed for the individual outcomes. Results: A total of nine published studies, one oral presentation, and our unpublished study were included in the analysis. Delayed surgery has better results than early surgery in terms of complete excision rate (delayed ES, 1.00; 95% CI, 0.97 1.00 vs. early ES, 0.96; 95% CI, 0.91 0.99), good functional outcome (delayed ES, 0.94; 95% CI, 0.86 0.99 vs. early ES, 0.68; 95% CI, 0.51 0.84), and mortality (delayed ES, 0.00; 95% CI, 0.00 0.01 vs. early ES, 0.04; 95% CI, 0.01 0.10). Heterogeneity was significant in the results of early surgery group, and no publication bias was found in the meta-analysis. Conclusion: Delayed surgery is superior to early surgery in achieving higher complete excision rate, good functional outcome, and reducing mortality. However, larger comparative studies are needed for subgroup analysis and for reducing the impact of various confounding factors.

Trends in Primary Anatomical Single-Bundle Anterior Cruciate Ligament Reconstruction Practice in Adult Patients Prevalent Among Arthroscopy Surgeons of Six Southern States of India.

Background: Although guidelines from multiple scientific studies decide the general trend in ACLR practice, there is often a variation between scientific guidelines and actual practice. Methods: A 17-member committee comprised of sports surgeons with experience of a minimum of 10 years of arthroscopy surgery finalized a survey questionnaire consisting of concepts in ACL tear management and perioperative trends, intraoperative and post-operative practices regarding single-bundle anatomic ACLR. The survey questionnaire was mailed to 584 registered sports surgeons in six states of south India. A single, non-modifiable response was collected from each member and analyzed. Results: 324 responses were received out of 584 members. A strong consensus was present regarding Hamstring tendons preference for ACLR, graft diameter ≥ 7.5 mm, viewing femoral footprint through the anterolateral portal, drilling femoral tunnel from anteromedial portal guided by ridges and remnants of femoral footprint using a freehand technique, suspensory devices to fix the graft in femur and interference screw in the tibia and post-operative bracing. A broad consensus was achieved in using a brace to minimize symptoms of instability of an ACL tear and antibiotic soaking of graft. There was no consensus regarding the timing of ACLR, preferred graft in athletes, pre-tensioning, extra-articular procedure, and return to sports. There was disagreement over hybrid tibial fixation and suture tapes to augment graft. Conclusion: Diverse practices continue to prevail in the management of ACL injuries. However, some of the consensuses reached in this survey match global practices. Contrasting or inconclusive practices should be explored for potential future research.

Transposition nasolabial flap: A versatile flap for sensate reconstruction of lip defects.

INTRODUCTION: Lip reconstruction aims at maintaining the function and aesthetics of the facial subunits. Sensation in the reconstructed lip helps in bolus formation, tactile discrimination, and thermal sensation. In this study, we aim to describe random pattern nasolabial flap for lip reconstruction using various functional parameters. METHODOLOGY: This is a retrospective study of 22 patients with carcinoma lip who underwent surgical resection and reconstruction with sensate nasolabial flap. Several clinicopathological parameters were studied. Outcome parameters like oral competence, tactile sensation, thermal sensitivity of reconstructed lip and speech outcomes were evaluated. RESULT: A functional outcome with 2-4 mm of two-point discrimination was obtained in 19 patients. All patients had intelligible speech. A mean sulcus depth of 19.59 mm was achieved. One patient had partial flap loss owing to wound infection. CONCLUSION: Random pattern senate nasolabial flap offers a good functional outcome by maintaining the tactile and thermal sensitivity.

Effect of fluconazole on the pharmacokinetics of a single dose of fedratinib in healthy adults.

PURPOSE: Fedratinib is an orally administered Janus kinase (JAK) 2-selective inhibitor for the treatment of adult patients with intermediate-2 or high-risk primary or secondary myelofibrosis. In vitro, fedratinib is predominantly metabolized by cytochrome P450 (CYP) 3A4 and to a lesser extent by CYP2C19. Coadministration of fedratinib with CYP3A4 inhibitors is predicted to increase systemic exposure to fedratinib. This study evaluated the effect of multiple doses of the dual CYP3A4 and CYP2C19 inhibitor, fluconazole, on the pharmacokinetics of a single dose of fedratinib. METHODS: In this non-randomized, fixed-sequence, open-label study, healthy adult participants first received a single oral dose of fedratinib 100 mg on day 1. Participants then received fluconazole 400 mg on day 10 and fluconazole 200 mg once daily on days 11-23, with a single oral dose of fedratinib 100 mg on day 18. Pharmacokinetic parameters were calculated for fedratinib administered with and without fluconazole. RESULTS: A total of 16 participants completed the study and were included in the pharmacokinetic population. Coadministration of fedratinib with fluconazole increased maximum observed plasma concentration (Cmax) and area under the plasma concentration-time curve from time 0 to the last quantifiable concentration (AUC0-t) of fedratinib by 21% and 56%, respectively, compared with fedratinib alone. Single oral doses of fedratinib 100 mg administered with or without fluconazole were well tolerated. CONCLUSIONS: Systemic exposure after a single oral dose of fedratinib was increased by up to 56% when fedratinib was coadministered with fluconazole compared with fedratinib alone. TRIAL REGISTRY: CLINICALTRIALS.GOV: NCT04702464.

Extra-Fortification of Zinc Upsets Vitellogenin Gene Expression and Antioxidant Status in Female of Clarias magur brooders.

The present experiment was designed to evaluate the effect of graded level of zinc on Vitellogenin gene (Vtg) expression and antioxidant enzymes in threatened catfish, Clarias magur (C. magur). One hundred and eighty female C. magur with an average weight of 145 ± 5 g were allocated in twelve cemented tanks with dimension 4.5 × 2 × 1 m for a period of 60 days. Fish were distributed in four groups with three replicates following the completely randomised design. The first group treated as control (C) fed with basal diet contained normal zinc level, and remaining groups were fed with basal diets having 50, 200 and 300 mg/kg zinc acetate and treated as T1, T2 and T3 respectively. To evaluate the effect of dietary zinc supplementation on Vtg gene expression, three sampling were carried out, I sampling (April, before starting the experimental trail), II sampling (May, after 1 month of feeding trail) and III sampling (June before breeding season). In the present study, a dose-dependent relationship between Vtg gene expression and zinc inclusion in the diet of threatened catfish, C. magur, was reported. Vtg gene expression increased in all groups from I sampling to II sampling but the highest Vtg gene expression was found in T1 group and the lowest in T3 group at II sampling. Vtg gene expression among the treatments differs significantly (P < 0.05) in each sampling. Accumulation of zinc was measured by Inductively Coupled Plasma Atomic Emission Spectroscopy (ICP-AES) in C. magur and it was reported that the significantly higher (P < 0.05) zinc was accumulated in the liver and ovary of T3 group as compared to other groups. The antioxidant enzyme activities (superoxide dismutase, SOD, catalase and GST) were also measured in different tissues (liver, gill and ovary) to evaluate the effect of extra-supplementation of zinc on the antioxidant status. In T3 group, SOD, catalase and GST activities were significantly higher than those in other groups. In the current study, serum glucose level was also measured and it was found in increasing trend with inclusion of zinc in the diet of C. magur. In the present study, it can be concluded that the zinc exhibits beneficial effect only up to 50 mg/kg. Thus, it is concluded that supplementation of zinc at 200 mg/kg or more disrupts Vtg gene expression and antioxidant status.

Trepanation revisited in COVID-19 era: A perspective on craniotomy during current pandemic, surgical technique, and complications avoidance.

Background: Craniotomy creates maximum aerosols threatening the health care workers (HCWs) of operation room. The technique of trepanation and measures to avoid complications has never been described in the literature. The time taken for craniotomy by different instruments has also never been compared. Methods: The study included only COVID-positive patients who underwent surgery. Craniotomy was performed using trephine, pneumatic/power drill (PD), and Hudson brace-Gigli saw (HB-GS). Trepanation as done in 32 patients. The generation of aerosols and time taken for craniotomy by these instruments was observed. The droplet spread over a waterproof graph paper of 10 × 10 sq. cm was calculated in 13 cases of all the three craniotomy methods. The technique of trepanation and maneuvers to overcome complications was discussed. Results: There was a gross difference in aerosol production and soiling of the surgical drapes, floor, surgeon's glove, gowns, face shield, goggles, etc. The average number of droplet aerosol in trepanation group was 4.76, 23.6 in drill and 21.3 in Gigli saw method. The average time taken for trepanation, PD, and HB-GS craniotomy was 4.8, 22.8, and 24.4 min, respectively. One mortality secondary to COVID was noted. All the HCWs assisting trepanation were negative for COVID-19 during postoperative follow-up of 7 days. However, 13 members of the surgical team which assisted in electric drill and HB-GS methods were COVID-positive. Conclusion: Trepanation should be the preferred method of craniotomy during COVID-19 pandemic as it is associated with the least aerosolization and is the most time efficient.

Time Taken for Symptom Recognition, First Consultation, Diagnosis and First Definitive Treatment and Its Associated Factors among Women with Breast Cancer.

BACKGROUND: Breast cancer patients in Malaysia often present late, delaying diagnosis and treatment. Decisions on health-seeking behaviour are influenced by a complex interplay of several factors. Early detection and subsequent successful treatment are the main goal in order to reduce breast cancer mortality. The aims of this study were to identify the time taken by women with breast cancer for consultation, diagnosis and first definitive treatment and the factors associated with the initiation of definitive treatment. METHODS: In this cohort study, we interviewed 328 women with histologically confirmed breast cancer at five medical centres in Malaysia. Times were measured from recognition of symptoms to first consultation to diagnosis and to the first definitive treatment. The event was initiation of definitive treatment. Data was analysed using multivariable Cox proportional hazards regression. RESULTS: The mean age was 47.9 (standard deviation 9.4) years and 79.9% were ethnic Malays. The median follow-up time was 6.9 months. The median times for first doctor consultation, diagnosis and initiation of treatment were 2 months, 5.5 months and 2.4 weeks, respectively. The percentage of consultation delay more than a month was 66.8%, diagnosis delay more than three months was 73.2% and treatment delay more than one month was 11.6%. Factors associated with not initiating the definitive treatment were pregnancy (adjusted hazard ratio (AHR) 1.75; 95% Confidence Interval (CI): 1.07, 2.88), taking complementary alternative medicine (AHR 1.45; 95% CI: 1.15, 1.83), initial refusal of mastectomy (AHR 3.49; 95% CI: 2.38, 5.13) and undergoing lumpectomy prior to definitive treatment (AHR 1.62; 95% CI: 1.16, 2.28). CONCLUSIONS: Delays in diagnosis and consultation were more serious than treatment delays. Most respondents would accept treatment immediately after diagnosis. Respondents themselves were responsible for a large proportion of the delays. This study was successful in understanding the process of breast cancer patients' experience, from symptoms recognition to consultation, diagnosis and treatment.

Impact of fedratinib on the pharmacokinetics of transporter probe substrates using a cocktail approach.

INTRODUCTION: Fedratinib, an oral, selective Janus kinase 2 inhibitor, has been shown to inhibit P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion transporting polypeptide (OATP) 1B1, OATP1B3, organic cation transporter (OCT) 2, and multidrug and toxin extrusion (MATE) 1 and MATE2-K in vitro. The objective of this study was to evaluate the influence of fedratinib on the pharmacokinetics (PK) of digoxin (P-gp substrate), rosuvastatin (OATP1B1/1B3 and BCRP substrate), and metformin (OCT2 and MATE1/2-K substrate). METHODS: In this nonrandomized, fixed-sequence, open-label study, 24 healthy adult participants received single oral doses of digoxin 0.25 mg, rosuvastatin 10 mg, and metformin 1000 mg administered as a drug cocktail (day 1, period 1). After a 6-day washout, participants received oral fedratinib 600 mg 1 h before the cocktail on day 7 (period 2). An oral glucose tolerance test (OGTT) was performed to determine possible influences of fedratinib on the antihyperglycemic effect of metformin. RESULTS: Plasma exposure to the three probe drugs was generally comparable in the presence or absence of fedratinib. Reduced metformin renal clearance by 36% and slightly higher plasma glucose levels after OGTT were observed in the presence of fedratinib. Single oral doses of the cocktail ± fedratinib were generally well tolerated. CONCLUSIONS: These results suggest that fedratinib has minimal impact on the exposure of P-gp, BCRP, OATP1B1/1B3, OCT2, and MATE1/2-K substrates. Since renal clearance of metformin was decreased in the presence of fedratinib, caution should be exercised in using coadministered drugs that are renally excreted via OCT2 and MATEs. TRIAL REGISTRATION: Clinicaltrials.gov NCT04231435 on January 18, 2020.

Underlying Mechanisms of Allopurinol in Eliminating Renal Toxicity Induced by Melamine-Uric Acid Complex Formation: A Computational Study.

Using molecular dynamics, we address uric acid (UA) replacement by a model small-molecule inhibitor, allopurinol (AP), from its aggregated cluster in a columnar fashion. Experimentally it has been affirmed that AP is efficient in preventing UA-mediated renal stone formation. However, no study has presented the underlying mechanisms yet. Hence, a theoretical approach is presented for mapping the AP, which binds to melamine (MM) and UA clusters. In AP's presence, the higher-order cluster of UA molecules turns into a lower-order cluster, which "drags" fewer MM to them. Consequently, the MM-UA composite structure gets reduced. It is worth noting that UA-AP and AP-MM hydrogen-bonding interactions often play an essential role in reducing the UA-MM cluster size. Interestingly, an AP around UA makes a pillar-like structure, confirmed by defining the point-plane distribution function. The decomposition of the preferential interaction by Kirkwood-Buff integral into different angles like 0°-30°, 30°-60°, and 60°-90° firmly establishes the phenomenon mentioned above. However, the structural order for such π-stacking interactions between AP and UA molecules is not hierarchical but rather more spontaneous. The driving force behind UA-AP-MM composite formation is the favorable complexation energy that can be inferred by computing pairwise binding free energies for all possible combinations. Performing enhanced sampling and quantum calculations further confirms the evidence for UA degradation.

Effects of strong and moderate CYP3A4 inducers on the pharmacokinetics of fedratinib in healthy adult participants.

PURPOSE: Fedratinib is an oral and selective Janus kinase 2 inhibitor that is indicated for treatment of adults with intermediate-2 or high-risk primary or secondary myelofibrosis. Fedratinib is metabolized by cytochrome P450s (CYPs), primarily CYP3A4. The objective of this study was to determine the effects of the strong CYP3A4 inducer rifampin and moderate CYP3A4 inducer efavirenz on the pharmacokinetics of single doses of fedratinib. METHODS: This Phase 1, open-label, two-part study (Part 1 for rifampin and Part 2 for efavirenz) was conducted in healthy adult men and women. A single dose of fedratinib (500 mg) was administered on Day 1. Participants received rifampin 600 mg daily or efavirenz 600 mg daily on Days 9-18. On Day 17, a single dose of fedratinib (500 mg) was coadministered with rifampin or efavirenz. Plasma fedratinib concentrations were measured using validated liquid chromatography-tandem mass spectrometry. RESULTS: Maximum observed plasma fedratinib concentrations were lowered by approximately 70% and 30% during coadministration with rifampin or efavirenz, respectively, compared with fedratinib alone. Geometric means of fedratinib area under the plasma concentration-time curve from 0 to infinity were decreased by 81% (90% confidence interval [CI], 77-83%) and 47% (90% CI, 40-53%) during coadministration with rifampin or efavirenz, respectively. Fedratinib was generally well tolerated when administered alone or in combination with rifampin or efavirenz. CONCLUSION: Significant reductions in fedratinib exposure were observed in the presence of strong or moderate CYP3A4 inducers. These results suggest that agents that are strong or moderate inducers of CYP3A4 should be avoided when coadministered with fedratinib. TRIAL REGISTRATION NUMBER: NCT03983239 (Registration date: June 12, 2019).

Evaluation of the Potential for QTc Prolongation With Repeated Oral Doses of Fedratinib in Patients With Advanced Solid Tumors.

The impact of repeated daily 500-mg fedratinib (an oral selective Janus kinase [JAK] 2 inhibitor) on QTc and other electrocardiogram (ECG) parameters was assessed in 60 patients with advanced solid tumors. Patients received placebo on day 1 and fedratinib 500 mg daily for 14 days. Concentration-QTc analysis was performed with change-from-baseline QTc corrected by Fridericia's formula (ΔQTcF) as the dependent variable. Fedratinib median time to maximum plasma concentration (Cmax ) was observed 3 hours postdose on day 15. The largest difference between means for fedratinib and placebo was 0.5 bpm (90%CI, -2.75 to 3.72 bpm) for heart rate (3 hours postdose) and 4.3 milliseconds (90%CI, 1.04-7.60 milliseconds) for QTcF (4 hours postdose). The estimated slope of the fedratinib concentration-QTcF relationship was shallow and not statistically significant: -0.0005 milliseconds per ng/mL (90%CI, -0.00145 to 0.00050 milliseconds per ng/mL). Predicted fedratinib placebo-corrected ΔQTcF was 0.6 milliseconds (90%CI, -1.80 to 2.93 milliseconds) at the geometric mean of the observed Cmax (3615 ng/mL). Fedratinib did not affect PR or QRS intervals. No patients had QTcF > 60 milliseconds, and no patients experienced QTcF ≥ 500 milliseconds. Fedratinib did not cause clinically relevant ECG effects or QTc prolongation. Safety findings were consistent with the known safety profile.

Antibacterial and antioomycete activities of a novel designed RY12WY peptide against fish pathogens.

In the present study, we have designed and synthesized a short compositionally simple peptide RY12WY having potent antimicrobial activity. The molecular docking study results showed that peptide has a strong affinity towards two protein targets of A. sobria; aerolysin and outer membrane protein (OMP). The MIC values ranged from 0.98 to 500 µM and MBC values ranged from 4 to 650 µM against the selected bacterial and fungal pathogens. The intense antimicrobial activity of RY12WY is reported against A. sobria, A. hydrophila, E. tarda, S. aureus, V. parahaemolyticus, P. aeruginosa and E.coli at low concentration.The peptide also showed good activity against A. salmonicida and S. parasitica zoospores. The peptide retained its antimicrobial activity at higher temperatures. Besides, it was active in the presence of physiological salts and serum.The peptide showed negligible haemolytic activity at 125 µM and HC50 was found to be 1437.10 µM. The DNA binding assay indicated that peptide can bind with the genetic material of the bacteria and may inhibit its replication. The bacterial viability assay reported that the peptide interferes with bacterial membrane integrity. To conclude, the results suggest that RY12WY could be a promising therapeutic agent in aquaculture and has possible application in food processing industry which warrants higher temperatures.

Endoscopic Excision of Intraventricular Neurocysticercosis Cyst with an Angiocatheter: A Retrospective Analysis.

INTRODUCTION: An intraventricular cysticercus cyst is observed in 7%-30% patients of neurocysticercosis (NCC). Apart from causing arachnoiditis, intraventricular NCC (IVNCC) can cause sudden death due to acute episodes of hydrocephalus. Various treatment modalities available are external cerebrospinal fluid (CSF) diversion, microsurgical removal, and endoscopic management. There is no consensus regarding the optimal surgical treatment strategy. We are presenting our experience by doing a retrospective analysis of 26 patients having endoscopic removal of IVNCC with a rigid endoscope and angiocatheter. AIM: The aim of this study is to evaluate the results of neuroendoscopy in restoring the CSF pathway and removal of the cyst in patients of IVNCC. MATERIALS AND METHODS: Retrospective analysis of clinical record and follow-up of 26 patients of IVNCC who were treated endoscopically between 2010 and 2018 was done. The diagnosis of IVNCC was made based on contrast enhanced magnetic resonance imaging of the brain. Transcranial endoscopy with 0° endoscope was performed through the frontal burr hole. Third ventriculostomy and removal of the cysticercus cyst with angiocatheter were the procedures done. RESULTS: The success rate of intraventricular cyst excision, whether complete or partial, was 100% (14/14) in the third ventricular cyst, 62.5% (5/8) in the fourth ventricular cyst and 100% (4/4) in the lateral ventricular cyst. The overall success rate of cyst excision by endoscopy was 88.46%. The overall successful CSF flow pathway was established in 88.46% cases. The mean duration of follow-up was 44 months, and all the patients were found symptom free in the follow-up period. CONCLUSION: Neuroendoscopy, being a single burr hole technique successfully providing internal CSF diversion and cyst removal, is the treatment modality of choice for IVNCC.

Physiologically based pharmacokinetic modeling to assess metabolic drug-drug interaction risks and inform the drug label for fedratinib.

PURPOSE: Fedratinib (INREBIC®), a Janus kinase 2 inhibitor, is approved in the United States to treat patients with myelofibrosis. Fedratinib is not only a substrate of cytochrome P450 (CYP) enzymes, but also exhibits complex auto-inhibition, time-dependent inhibition, or mixed inhibition/induction of CYP enzymes including CYP3A. Therefore, a mechanistic modeling approach was used to characterize pharmacokinetic (PK) properties and assess drug-drug interaction (DDI) potentials for fedratinib under clinical scenarios. METHODS: The physiologically based pharmacokinetic (PBPK) model of fedratinib was constructed in Simcyp® (V17R1) by integrating available in vitro and in vivo information and was further parameterized and validated by using clinical PK data. RESULTS: The validated PBPK model was applied to predict DDIs between fedratinib and CYP modulators or substrates. The model simulations indicated that the fedratinib-as-victim DDI extent in terms of geometric mean area under curve (AUC) at steady state is about twofold or 1.2-fold when strong or moderate CYP3A4 inhibitors, respectively, are co-administered with repeated doses of fedratinib. In addition, the PBPK model successfully captured the perpetrator DDI effect of fedratinib on a sensitive CY3A4 substrate midazolam and predicted minor effects of fedratinib on CYP2C8/9 substrates. CONCLUSIONS: The PBPK-DDI model of fedratinib facilitated drug development by identifying DDI potential, optimizing clinical study designs, supporting waivers for clinical studies, and informing drug label claims. Fedratinib dose should be reduced to 200 mg QD when a strong CYP3A4 inhibitor is co-administered and then re-escalated to 400 mg in a stepwise manner as tolerated after the strong CYP3A4 inhibitor is discontinued.

Excretion balance and pharmacokinetics following a single oral dose of [14C]-fedratinib in healthy subjects.

PURPOSE: Fedratinib is an oral and selective kinase inhibitor with activity against wild type and mutationally activated Janus kinase 2 and FMS-like tyrosine kinase 3, for the treatment of adult patients with intermediate-2 or high-risk primary or secondary myelofibrosis. This open-label mass balance study in healthy subjects investigated the excretion balance and systemic exposure of radioactivity after oral administration of [14C]-fedratinib; and the pharmacokinetics of fedratinib and its contribution to overall exposure of radioactivity. METHODS: Six healthy males received a single oral dose of 200 mg [14C]-fedratinib base (2.775 MBq, 75 µCi) as a solution. Blood, urine and feces samples were collected for up to 35 day postdose. Urine and feces samples were collected until the 24-h excretion of radioactivity fell below 0.5% of administered dose (at least 14 day postdose). Expired air was collected up to 8-h postdose. Total radioactivity (blood, plasma, urine, feces, and expired air) and fedratinib concentrations (plasma) were measured. RESULTS: Approximately 77% (23% unchanged) of fedratinib derived radioactivity was excreted in feces and 5% (3% unchanged) was excreted in urine. Excretion via expired air was negligible. The time to maximum concentration for both total radioactivity and parent drug was similar, with unchanged drug representing the majority of the circulating radioactivity. The ratio of blood to plasma concentration of radioactivity ranged from 0.615 to 0.753 indicating limited distribution of fedratinib and/or its metabolites into red blood cells. CONCLUSIONS: Fedratinib derived radioactivity was primarily excreted in feces following a single oral dose of radiolabeled fedratinib to healthy subjects.