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MicroRNAs (miRNAs) regulate gene expression through RNA interference. Consequently, miRNA inhibitors, such as anti-miRNA oligonucleotides (AMOs), have attracted attention for treating miRNA overexpression. To achieve efficient inhibition, we developed 2-amino-6-vinylpurine (AVP) nucleosides that form covalent bonds with uridine counterparts in RNA. We demonstrated that mRNA cross-linked with AVP-conjugated antisense oligonucleotides with AVP were protected from gene silencing by exogenous miRNA. However, endogenous miRNA function could not be inhibited in cells, probably because of slow cross-linking kinetics. We recently developed ADpVP, an AVP derivative bearing a 7-propynyl group - which boasts faster reaction rate than the original AVP. Here, we synthesized dADpVP - a deoxy analog of ADpVP - through a simplified synthesis protocol. Evaluation of the cross-linking reaction revealed that the reaction kinetics of dADpVP were comparable to those of ADpVP. In addition, structural analysis of the cross-linked adduct discovered N3 linkage against uridine. Incorporating dADpVP into two types of miRNA inhibitors revealed a marginal impact on AMO efficacy yet improved the performance of target site blockers. These results indicate the potential of cross-linking nucleosides for indirect miRNA function inhibition., (© 2024 The Authors. ChemBioChem published by Wiley-VCH GmbH.)

Background: Hereditary angioedema is a rare genetic disease characterized by severe and unpredictable swelling attacks. NTLA-2002 is an in vivo gene-editing therapy that is based on clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9. NTLA-2002 targets the gene encoding kallikrein B1 ( KLKB1 ). A single dose of NTLA-2002 may provide lifelong control of angioedema attacks., Methods: In this phase 2 portion of a phase 1-2 trial, we randomly assigned adults with hereditary angioedema in a 2:2:1 ratio to receive NTLA-2002 in a single dose of 25 mg or 50 mg or placebo. The primary end point was the number of angioedema attacks per month (the monthly attack rate) from week 1 through week 16. Secondary end points included safety, pharmacokinetics, and pharmacodynamics (i.e., the change from baseline in total plasma kallikrein protein level); exploratory end points included patient-reported outcomes., Results: Of the 27 patients who underwent randomization, 10 received 25 mg of NTLA-2002, 11 received 50 mg, and 6 received placebo. From week 1 through week 16, the estimated mean monthly attack rate was 0.70 (95% confidence interval [CI], 0.25 to 1.98) with 25 mg of NTLA-2002, 0.65 (95% CI, 0.24 to 1.76) with 50 mg, and 2.82 (95% CI, 0.80 to 9.89) with placebo; the difference in the estimated mean attack rate with NTLA-2002 as compared with placebo was -75% with 25 mg and -77% with 50 mg. Among patients who received NTLA-2002, 4 of the 10 patients who received 25 mg (40%) and 8 of the 11 who received 50 mg (73%) were attack-free with no additional treatment during the period from week 1 through week 16. The most common adverse events among patients who received NTLA-2002 were headache, fatigue, and nasopharyngitis. The mean percent change in total plasma kallikrein protein levels from baseline to week 16 was -55% with 25 mg and -86% with 50 mg; levels remained unchanged with placebo., Conclusions: NTLA-2002 administered in a single dose of 25 mg or 50 mg reduced angioedema attacks and led to robust and sustained reduction in total plasma kallikrein levels in patients with hereditary angioedema. These results support continued investigation in a larger phase 3 trial. (Funded by Intellia Therapeutics; ClinicalTrials.gov number, NCT05120830; EudraCT number, 2021-001693-33.)., (Copyright © 2024 Massachusetts Medical Society.)

Background: Hereditary angioedema is a rare genetic disease that leads to severe and unpredictable swelling attacks. NTLA-2002 is an in vivo gene-editing therapy based on clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9. NTLA-2002 targets the gene encoding kallikrein B1 ( KLKB1 ), with the goal of lifelong control of angioedema attacks after a single dose., Methods: In this phase 1 dose-escalation portion of a combined phase 1-2 trial of NTLA-2002 in adults with hereditary angioedema, we administered NTLA-2002 at a single dose of 25 mg, 50 mg, or 75 mg. The primary end points were the safety and side-effect profile of NTLA-2002 therapy. Secondary and exploratory end points included pharmacokinetics, pharmacodynamics, and clinical efficacy determined on the basis of investigator-confirmed angioedema attacks., Results: Three patients received 25 mg of NTLA-2002, four received 50 mg, and three received 75 mg. At all dose levels, the most common adverse events were infusion-related reactions and fatigue. No dose-limiting toxic effects, serious adverse events, grade 3 or higher adverse events, or clinically important laboratory findings were observed after the administration of NTLA-2002. Dose-dependent reductions in the total plasma kallikrein protein level were observed between baseline and the latest assessment, with a mean percentage change of -67% in the 25-mg group, -84% in the 50-mg group, and -95% in the 75-mg group. The mean percentage change in the number of angioedema attacks per month between baseline and weeks 1 through 16 (primary observation period) was -91% in the 25-mg group, -97% in the 50-mg group, and -80% in the 75-mg group. Among all the patients, the mean percentage change in the number of angioedema attacks per month from baseline through the latest assessment was -95%., Conclusions: In this small study, a single dose of NTLA-2002 led to robust, dose-dependent, and durable reductions in total plasma kallikrein levels, and no severe adverse events were observed. In exploratory analyses, reductions in the number of angioedema attacks per month were observed at all dose levels. (Funded by Intellia Therapeutics; ClinicalTrials.gov number, NCT05120830.)., (Copyright © 2024 Massachusetts Medical Society.)

We report radiation-induced lattice relaxation of the [Formula: see text]-Fe[Formula: see text]O[Formula: see text] and its associated alteration of particle morphology. The [Formula: see text]-Fe[Formula: see text]O[Formula: see text] was grown in solution by microwave hydrothermal synthesis technique in which more than half of the synthesized material was nanorods with axis along the (001) direction. Five sets of the synthesized [Formula: see text]-Fe[Formula: see text]O[Formula: see text] samples were irradiated using gamma-ray from [Formula: see text]Co cell with doses of 600 kGy, 700 kGy, 800 kGy, 900 kGy, and 1 MGy. The investigation of the pristine and gamma-irradiated samples was carried out using X-ray powder diffraction, transmission electron microscope, and electron paramagnetic resonance methods. Results showed that continuous alternation of radiation-induced lattice compression and expansion causes lattice relaxation. The morphology of the [Formula: see text]-Fe[Formula: see text]O[Formula: see text] nanorods was found to change with absorbed dose into buckyball-shaped particles in response to the alternation of the compression and expansion strain. The EPR results showed a correlation between distortion in the [Formula: see text]-[Formula: see text] octahedron structure and the relaxation of the lattice. The synthesis, growth, and relaxation are discussed in detail., (© 2023. Springer Nature Limited.)

Genome editing holds the potential for curative treatments of human disease, however, clinical realization has proven to be a challenging journey with incremental progress made up until recently. Over the last decade, advances in clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein (Cas) systems have provided the necessary breakthrough for genome editing in the clinic. The progress of investigational CRISPR therapies from bench to bedside reflects the culmination of multiple advances occurring in parallel, several of which intersect with clinical pharmacology and translation. Directing the CRISPR therapy to the intended site of action has necessitated novel delivery platforms, and this has resulted in special considerations for the complete characterization of distribution, metabolism, and excretion, as well as immunogenicity. Once at the site of action, CRISPR therapies aim to make permanent alterations to the genome and achieve therapeutically relevant effects with a single dose. This fundamental aspect of the mechanism of action for CRISPR therapies results in new considerations for clinical translation and dose selection. Early advances in model-informed development of CRISPR therapies have incorporated key facets of the mechanism of action and have captured hallmark features of clinical pharmacokinetics and pharmacodynamics from phase I investigations. Given the recent emergence of CRISPR therapies in clinical development, the landscape continues to evolve rapidly with ample opportunity for continued innovation. Here, we provide a snapshot of selected topics in clinical pharmacology and translation that has supported the advance of systemically administered in vivo and ex vivo CRISPR-based investigational therapies in the clinic., (© 2023 Intellia Therapeutics. Clinical Pharmacology & Therapeutics © 2023 American Society for Clinical Pharmacology and Therapeutics.)

Background: Pulmonary involvement is the most common leading cause of morbidity and mortality associated with systemic sclerosis. Therefore, identifying the various patterns of pulmonary affection is crucial in the clinical management of these patients. In the current study, we aim to investigate the patterns of interstitial lung disease (ILD) associated with SSc patients (SSc- ILD) and their relation to serologic markers and clinical parameters., Methods: A cross-sectional study was undertaken on thirty-four adult SSc patients who met the 2013 ACR/EULAR criteria for SSc and Forty healthy controls of matched age and sex. The patients were subjected to history taking, clinical examination, skin assessment using the modified Rodnan Skin Score (mRSS), chest x-ray (CXR), pulmonary function test (PFTs), and high resolution computed tomography of the chest (HRCT). Routine laboratory tests were conducted in addition to immunologic tests and an enzyme-linked immunosorbent assay (ELISA) to determine the IL-33 level., Results: ILD was found in 23 SSc patients (67.6%); 20 patients had diffuse type while 3 patients had limited type. Non-specific interstitial pneumonia (NSIP) was found in 56.5%, usual interstitial pneumonia (UIP) was found in 21.7%, pleuroparenchymal fibroelastosis (PPFE) was found in 8.7%, and organizing pneumonia (OP) with the mixed pattern was found in 13% of SSc patients. Additionally, the mean IL-33 level in SSc patients was 98±12.7 compared to 66.2±10.6 in the control group (p < 0.001), with ILD patients having a significantly higher level (101.7±13.4) than those without (90.4±6.2), and a strong positive correlation with mRSS., Conclusion: Even in asymptomatic patients with SSc, ILD is prevalent, with NSIP being the most common pattern. IL-33 could be considered a potential biomarker for predicting the presence of ILD in SSc patients., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

A systematic investigation on the isotopic and elemental signature, for both stable and radioactive elements, and mineral contents was performed to examine the characteristics of subsurface formations collected at different depths between 3.962 km and 4.115 km around deep-laying coal seams located under the Marmarica plateau in Egypt. Concentrations of major and minor oxides (Na 2 O, MgO, Al 2 O 3 , SiO 2 , SO 3 , K 2 O, CaO, TiO 2 , MnO, ΣFeO + Fe 2 O 3 , SrO, ZrO 2 , and BaO) were determined by X-ray fluorescence and dependencies among these concentrations revealed the type and sort of the formations. Organic contents were determined by Fourier Transform infrared spectroscopy to investigate the variation of the CO/CC bonding ratio with depth. Rare earth elements (REE), specifically Y, Sc, La, Ce, Pr, Nd, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, and Lu were determined by inductively coupled plasma mass spectrometry while actinoids were detected by the radioactive decay of its daughter nuclei. The results showed a high trapping of REE elements and actinoids in layers above the coal seams which indicates the occurrence of aqueous flow followed by possible sorption in these layers. The mobility of the fluid was investigated using the process radioactive decay series between Ra226 and Ac228 from one side and their daughters from the other side., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The interstrand crosslinking and threaded structures of nucleic acids have high potential in oligonucleotide therapeutics, chemical biology, and nanotechnology. For example, properly designed crosslinking structures provide high activity and nuclease resistance for anti-miRNAs. The noncovalent labeling and modification by the threaded structures are useful as new chemical biology tools. Photoreversible crosslinking creates smart materials, such as reversible photoresponsive gels and DNA origami objects. This review introduces the creation of interstrand crosslinking and threaded structures, such as catenanes and rotaxanes, based on hybridization-specific chemical reactions and their functions and perspectives.

Specific chemical reactions by enzymes acting on a nucleobase are realized by flipping the target base out of the helix. Similarly, artificial oligodeoxynucleotides (ODNs) can also induce the base flipping and a specific chemical reaction. We now report an easily prepared and unique structure-providing photo-cross-linking reaction by taking advantage of the base-flipping-out field formed by alkene-type base-flipping-inducing artificial bases. Two 3-arylethenyl-5-methyl-2-pyridone nucleosides with the Ph or An group were synthesized and incorporated into the ODNs. We found that the two Ph derivatives provided the cross-linked product in a high yield only by a 10 s photoirradiation when their alkenes overlap each other in the duplex DNA. The highly efficient reaction enabled forming a cross-linked product even when using the duplex with a low T m value.

Crosslinking reactions to nucleic acids are an effective way to prepare stable complexes formed by covalent bonding. We demonstrated that fully 2'-O-methylated (2'-OMe) RNAs having a 2-amino-6-vinylpurine (AVP) exhibited an efficient crosslinking to uracil in the target RNA. Recently, we reported the preparation of crosslinked 2'-OMe RNA duplexes using AVP and the anti-miRNA oligonucleotides (AMOs) containing crosslinked duplexes at the terminal positions. These AMOs exhibited efficient microRNA (miRNA) inhibition at very low concentrations. In this article, we describe the chemical synthesis of 2'-OMe oligonucleotides containing AVP and preparation of the AMOs bearing crosslinked 2'-OMe RNA duplexes using AVP. In addition, we describe in detail the miRNA inhibition assay using these AMOs. © 2022 Wiley Periodicals LLC. Basic Protocol 1: Synthesis of phosphoramidite of 2-amino-6-vinylguanosine derivative Basic Protocol 2: Synthesis of AVP-2'-OMe RNA Basic Protocol 3: Evaluation of the crosslink reactivity of CFO containing AVP to the 2'-OMe RNA and preparation of AMOs containing crosslinked duplex Basic Protocol 4: miRNA inhibition assays., (© 2022 Wiley Periodicals LLC.)

Introduction: Extra-pulmonary manifestations of the Coronavirus disease of 2019 (COVID-19) have been increasingly reported, especially gastrointestinal and hepatic system dysfunction. The concern of faecal-oral transmission for COVID-19 was raised., Aim: To study the trend of faecal calprotectin in COVID-19 patients with intestinal symptoms., Material and Methods: Forty confirmed cases of COVID-19 infection presenting with diarrhoea were subjected to a thorough history taking, clinical examination, and routine laboratory investigations. They were treated according to the Egyptian MOH guidelines. Faecal calprotectin (FC) concentration was measured at initial presentation and after 3 months. Those who had persistently elevated levels ≥ 200 µg/g were subjected to colonoscopic examination and histopathological examination. Forty confirmed cases of COVID-19 without diarrhoea were recruited as a control group in the initial FC evaluation., Results: Faecal calprotectin was found to be significantly elevated in the studied COVID-19 patients who presented with diarrhoea, with a mean value 260 ±80 µg/g compared to the those without diarrhoea, with a mean value of 31.6 ±12.9 µg/g ( p < 0.001). Moreover, 20% (8 patients) had an elevated level exceeding 200 µg/g 3 months after recovery; among them, 5 patients showed mild colonoscopic changes whereas 3 patients showed severe ileocolitis. Out of the 3 patients with marked ileocolitis, 2 showed histopathological changes raising the diagnosis of Crohn's disease., Conclusions: Faecal calprotectin was found to be elevated in COVID-19 patients with intestinal symptoms, especially diarrhoea, with or without colonoscopic and histopathological changes., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 Termedia.)

The interstrand crosslinking of nucleic acids is one of the strategies to create the stable complex between an oligonucleotide and RNA by covalent bond formation. We previously reported that fully 2'-O-methylated (2'-OMe) RNAs having the 2-amino-6-vinylpurine (AVP) exhibited an efficient crosslinking to uracil in the target RNA. In this study, we established a chemical method to efficiently synthesize the crosslinked 2'-OMe RNA duplexes using AVP and prepared the anti-miRNA oligonucleotides (AMOs) containing the antisense targeting miR-21 and crosslinked duplex at the terminal sequences. These AMOs showed a markedly higher anti miRNA activity than that of the commercially-available miR-21 inhibitor which has locked nucleic acid (LNA) residues., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Purpose: Resistance to treatment with endocrine therapy in patients with HR + , HER2 - advanced breast cancer (ABC) is common and dual inhibition of CDK4/6 and PI3K pathways may delay the development of resistance. This phase Ib trial evaluates the safety and tolerability of triple and double regimens containing the CDK4/6 inhibitor ribociclib., Patients and Methods: In this open-label, multicenter, phase Ib study, 70 postmenopausal women with HR + , HER2 - ABC were enrolled into one of four treatment combinations: ribociclib (once daily, 3 weeks on, 1 week off) plus fulvestrant; ribociclib (continuous dosing) plus fulvestrant; ribociclib plus alpelisib plus fulvestrant; or ribociclib plus buparlisib plus fulvestrant., Results: The recommended phase II dose (RP2D) of ribociclib was confirmed to be 600 mg (3 weeks on, 1 week off) and 400 mg (continuous dosing) plus fulvestrant 500 mg. For the triple combination with buparlisib, the RP2D was ribociclib 400 mg plus buparlisib 30 mg plus fulvestrant 500 mg. Enrollment for the triple combinations was stopped due to unexpected toxicity. No RP2D was determined for the alpelisib combination. The safety profiles of the ribociclib plus fulvestrant combinations were consistent with those in previous studies. There was no marked difference in ribociclib exposure in the presence of triple-combination partners. The highest overall response rate was seen in the buparlisib triple combination (25.0%; 95% confidence interval, 9.8-46.7)., Conclusions: Ribociclib plus fulvestrant demonstrated safety in the treatment of patients with HR + , HER2 - ABC. Triple combinations with alpelisib or buparlisib plus fulvestrant are not recommended for phase II investigation. See related commentary by Clark et al., p. 371 ., (©2020 American Association for Cancer Research.)

Ribociclib, a selective and potent cyclin-dependent kinase 4/6 inhibitor, has demonstrated safety and efficacy in combination with endocrine therapy in hormone receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer. In 2 open-label crossover studies in healthy participants, the absolute bioavailability of a single oral dose of a ribociclib 600-mg tablet (n = 16) was compared with a single intravenous ribociclib infusion of 150 mg (n = 16), and the bioequivalence of a ribociclib 600-mg tablet (n = 31) and a ribociclib 600-mg capsule (n = 31) was evaluated. The pharmacokinetics of ribociclib and its major metabolite, LEQ803, were assessed in both studies. The oral bioavailability of the 600-mg ribociclib tablet was 65.8% (90% confidence interval [CI], 59.1-73.2%). The geometric mean systemic clearance of ribociclib was moderate (40.2 L/h; 27.4% intersubject variability [CV%]) compared with hepatic blood flow, and the geometric mean volume of distribution was high (979 L; 25.2 CV%). LEQ803-to-ribociclib metabolic ratios were 0.198 for the oral administration and 0.125 for intravenous infusion. Bioequivalence of the tablet and capsule formulations was demonstrated for ribociclib. The geometric mean ratios of maximum concentration and area under the curve from time 0 to last quantifiable concentration and to infinity were 1.01, 1.00, and 0.937, respectively, within the predefined bioequivalence range of 0.80 to 1.25. The median time to reach maximum concentration was 3 hours with both formulations. No serious adverse events were observed in either study., (© 2020, The American College of Clinical Pharmacology.)

Objective: To discover the possibility of using microRNA155 (miRNA155) expression level as a biomarker of Behçet's Disease (BD) activity or remission., Methods: Thirty BD patients' white blood cells (WBCs) miRNA155 expression was measured and compared to WBCs miRNA155 expression in 15 healthy subjects. Assessment of disease activity was done using Behçet's Disease Current Activity Form (BDCAF)., Results: miRNA155 expression significantly decreases with the increase of BD activity scored by BDCAF., Conclusion: Increased miRNA155 may be used as a biomarker of BD remission and thus in the disease follow up. There could be a prospect of treating the disease via microRNA 155 effect enhancement.

Background: Efavirenz (EFV) has been associated with torsade de pointes despite marginal QT interval lengthening. Since EFV is metabolized by the cytochrome P450 (CYP) 2B6 enzyme, we hypothesized that EFV would lengthen the rate-corrected QT (QTcF) interval in carriers of the CYP2B6*6 decreased functional allele., Objective: The primary objective of this study was to evaluate EFV-associated QT interval changes with regard to CYP2B6 genotype and to explore mechanisms of QT interval lengthening., Methods: EFV was administered to healthy volunteers (n = 57) as a single 600 mg dose followed by multiple doses to steady-state. Subjects were genotyped for known CYP2B6 alleles and ECGs and EFV plasma concentrations were obtained serially. Whole-cell, voltage-clamp experiments were performed on cells stably expressing hERG and exposed to EFV in the presence and absence of CYP2B6 expression., Results: EFV demonstrated a gene-dose effect and exceeded the FDA criteria for QTcF interval prolongation in CYP2B6*6/*6 carriers. The largest mean time-matched differences ∆∆QTcF were observed at 6 hours (14 milliseconds; 95% CI [1; 27]), 12 hours (18 milliseconds; 95% CI [-4; 40]), and 18 hours (6 milliseconds; 95% CI [-1; 14]) in the CYP2B6*6/*6 genotype. EFV concentrations exceeding 0.4 μg/mL significantly inhibited outward hERG tail currents (P < 0.05)., Conclusions: This study demonstrates that homozygous carriers of CYP2B6*6 allele may be at increased risk for EFV-induced QTcF interval prolongation via inhibition of hERG., (© 2016 Wiley Periodicals, Inc.)

Background: Abundant experimental evidence indicates overproduction of angiotensin II in the injured liver, and a role in stimulation of hepatic stellate cell (HSC) activation and fibrogenesis thereby, representing an attractive antifibrotic target. The aim of this study was to examine the antifibrotic effect of losartan on histopathologic level in chronic HCV patients., Methods: A prospective study on fifty patients with chronic HCV and liver fibrosis proved by liver biopsy was conducted. They included patients who did not respond (n=36) or comply (n=2) or receive therapy due to established cirrhosis (n=10), or refused to receive (n=2) combined interferon and ribavirin therapy. They were divided randomly into 2 groups. The 1(st) group (n=25) was given losartan 50 mg OD for 1 year and the 2(nd) group (25 patients) was given silymarin, 140 mg t.i.d., (silymarin group). Liver biopsy was done at baseline and 1 year from the onset of treatment (end of study)., Results: In the second liver biopsy after 1 year, the decrease in fibrosis stage was significantly different between losartan group and silymarin group (a decrease of 1.88±0.96 (50.9%) vs. 0.45±0.93 (11.7%), respectively; P<0.01). In patients treated with losartan, regression in fibrosis stage was observed in 14/16 patients vs. 2/11 in silymarin group (P<0.01). No differences were observed in inflammation grades in both groups. A significant increase in albumin and prothrombin levels and a decrease in systolic blood pressure were found in losartan but not in silymarin group (P=0.009, 0.001 & 0.018 respectively and P=0.158, 0.603 & 0.288, respectively)., Conclusions: Histopathological scores showed that losartan had an inhibitory effect on progression and even led to regression of fibrosis stage but had no effect on the grade of inflammation.

Introduction: Biliary peritonitis complicating blunt hepatic trauma is a rare but potentially lethal condition., Presentation of Case: A 17-year old male patient who sustained a complex grade IV blunt hepatic trauma presented with severe haemorrhagic shock after an initial laparotomy in another hospital. An urgent exploratory laparotomy revealed a shattered posterior section of the right liver and suture haemostasis of the lacerated liver surface was performed. Postoperatively, the patient developed generalized biliary peritonitis and another laparotomy with peritoneal lavage and drainage was performed on postoperative day 12. However, ongoing manifestations of peritonitis and sepsis necessitated a third laparotomy 6 days later. This revealed ongoing biliary peritonitis due to major intra-hepatic bile duct injury. A partial hepatectomy with intra-operative trans-hepatic biliary stenting was undertaken. Postoperative recovery was uneventful and the biliary fistula healed completely by the end of the second postoperative week., Discussion: Major intra-hepatic bile duct injury following blunt hepatic trauma is an extremely rare cause of biliary peritonitis., Conclusion: The combination of partial hepatectomy with intra-operative trans-hepatic biliary stenting proved to be a safe and effective method for treatment of biliary peritonitis due to major intra-hepatic bile duct injury following blunt hepatic trauma when non-operative management fails., (Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The purpose of this study was to determine the demographic and pharmacogenetic covariates that influence the disposition of efavirenz (EFV) and its major metabolites. A population pharmacokinetic (PK) model was developed from a randomized, cross-over, drug-interaction study in healthy male Korean subjects (n = 17). Plasma concentrations of EFV and its hydroxy-metabolites (0-120 hours) were measured by LC/MS/MS. Genomic DNA was genotyped for variants in the cytochrome P450 (CYP) 2A6, 2B6, 3A5, and MDR1 genes. A PK model was built in a stepwise procedure using nonlinear mixed effect modeling in NONMEM 7. The covariate model was built using the generalized additive modeling and forward selection-backward elimination. Model-based simulations were performed to predict EFV steady-state concentrations following 200, 400, and 600 mg daily oral dose among different CYP2B6 genotypes. The final model included only CYP2B6 genotype as a covariate that predicts EFV clearance through the formation of 8-OH EFV that represented 65% to 80% of EFV clearance. The total clearance of EFV in CYP2B6*6/*6 genotype was ∼30% lower than CYP2B6*1/*1 or CYP2B6*1/*6 alleles (P < .001). Clopidogrel reduced both formation and elimination clearances of 8-OH EFV by 22% and 19%, respectively (P = .033 and .041). Other demographics and genotype of accessory CYP pathways did not predict EFV or metabolites PK. CYP2B6 genotype was the only significant predictor of EFV disposition. The developed model may serve as the foundation for further exploration of pharmacogenetic-based dosing of EFV., (© 2013, The American College of Clinical Pharmacology.)

Shoulder hemiarthroplasty is a salvage treatment for comminuted fracture of the humerus especially in elderly patients. Several factors contribute to the final outcome like bone quality and tuberosity reposition. Timing of the surgery is considered one of these factors. This study was done to assess the effect of delaying the surgery up to 2 weeks on the final outcome. This retrospective study was done on 33 patients with four-part fracture of the humerus, divided into two groups, group 1 (17 patients) who had surgery within the first 3 days after trauma, and group 2 (16 patients) who had surgery within the second week after injury. Operations were done by the same surgeon, same technique, and same implant. Constant score was used to assess the final follow-up, and there was a significant better result for group one especially in the items of range of movements and power.

Neglected anterior shoulder dislocation is a rare condition; reduction usually requires an open procedure. There is usually a concurrent Hill-Sachs lesion, with the humeral head impaled over the anterior rim of the glenoid. Large, engaging Hill-Sachs lesions can contribute to continued shoulder instability, and therefore require a specific action. Reconstruction of the humeral head with an osteochondral allograft has been advocated, but allografts are not easily available in some countries, such as Egypt. For this reason, I switched to the open infraspinatus remplissage technique. I report the results with this technique, in four young adult patients who presented with a locked anterior shoulder dislocation, which had been left unreduced for 10 to 20 weeks. The infraspinatus tendon was pulled into the humeral defect with a four limbs suture anchor; as a result, the lesion became extra-articular. A Putti-Platt procedure was added to obtain anterior stability, except in one patient with a concurrent glenoid defect which required a Latarjet procedure. The mean follow-up period was 32 months, without recurrence or other complications. The mean postoperative Constant score was 74, and the range of motion was satisfactory, with a functional range of external rotation.

Introduction: The failure of a humeral fracture to unite after surgical treatment may be due to many factors. When there are additional complications of infection, treatment by conventional methods of internal fixation becomes very difficult., Materials and Methods: We treated 8 infected non-union of diaphyseal fracture of the humerus by the Orthofix external fixator. All had previous surgical treatment. Non-union followed plating in 6 cases and in 2 cases after the external fixator. All patients had pain, at least one sinus discharging pus and severe functional impairment of the affected arm. There were 6 men and 2 women with a mean age 40.6 years., Results: Bone union was achieved in all cases. The mean time to union was 4.5 months (range, 2 to 8). Patients expressed high levels of satisfaction with the outcome, despite relatively modest improvement in pain and function, mainly because of long standing infection and intractable non-union. There were no major pin tract problems requiring the removal of the Schanz screws. Radial nerve palsy developed in 1 patient who recovered spontaneously. No patient required an additional bone grafting procedure., Conclusion: The use of the Orthofix external fixator without bone grafting was successful in the treatment of infected non-union of the humeral shaft. It shortened the duration of hospitalisation and immobilisation with moderate functional recovery.