Punctate inner choroidopathy in common variable immunodeficiency associated with a pathogenic variant in the tumour necrosis factor receptor superfamily 13b (TNFRSF13B) gene - Case report and review of the literature.

BACKGROUND: Common variable immunodeficiency (CVID) has been recognised as the most common primary immunodeficiency in adulthood, and is characterised by increased susceptibility to infection, autoimmunity and increased risk of malignancies. Although ocular manifestations are not common in CVID, rare associated inflammatory eye conditions have been reported including submacular choroiditis. OBJECTIVE: To report a case of punctate inner choroidopathy in a patient with common variable immunodeficiency. CASE PRESENTATION: A 40-year-old lady with CVID and associated autoimmune thrombocytopenia, who was treated with immunoglobulin replacement and Eltrombopag, experienced gradually deteriorating right eye vision. Fundal examination and optical coherence tomography (OCT) revealed right multifocal retinal choroidal lesions consistent with a diagnosis of unilateral punctate inner choroidopathy (PIC) with secondary choroidal neovascularisation (CNV). Anti-VEGF injections led to stabilised fundal appearances. Genetic testing revealed a heterozygous sequence change c.260 T > Ap.(IIe87Asn), pathogenic variant in the Tumour Necrosis Factor Superfamily 13B (TNFRSF13B) gene, which is reported as being associated with ∼10% of CVID cases. CONCLUSION: Autoimmunity may be the dominant clinical presenting feature of CVID. Punctuate inner choroidopathy is an idiopathic inflammatory chorioretinopathy, and to the best of our knowledge, has not been previously reported in CVID. A better understanding of the molecular bases of autoimmune diseases in CVID may provide novel therapeutic targets for autoimmune diseases in this patient population.

Switching from rivaroxaban to warfarin: an open label pharmacodynamic study in healthy subjects.

AIMS: The primary objective was to explore the pharmacodynamic changes during transition from rivaroxaban to warfarin in healthy subjects. Safety, tolerability and pharmacokinetics were assessed as secondary objectives. METHODS: An open label, non-randomized, sequential two period study. In treatment period 1 (TP1), subjects received rivaroxaban 20 mg once daily (5 days), followed by co-administration with a warfarin loading dose regimen of 5 or 10 mg (for the 10 mg regimen, the dose could be uptitrated to attain target international normalized ratio [INR] ≥2.0) once daily (2-4 days). When trough INR values ≥2.0 were attained, rivaroxaban was discontinued and warfarin treatment continued as monotherapy (INR 2.0-3.0). During treatment period 2, subjects received the same warfarin regimen as in TP1, but without rivaroxaban. RESULTS: During co-administration, maximum INR and prothrombin time (PT) values were higher than with rivaroxaban or warfarin monotherapy. The mean maximum effect (Emax ) for INR after co-administration was 2.79-4.15 (mean PT Emax 41.0-62.7 s), compared with 1.41-1.74 (mean PT Emax 20.1-25.2 s) for warfarin alone. However, rivaroxaban had the smallest effect on INR at trough rivaroxaban concentrations. Neither rivaroxaban nor warfarin significantly affected maximum plasma concentrations of the other drug. CONCLUSIONS: The combined pharmacodynamic effects during co-administration of rivaroxaban and warfarin were greater than additive, but the pharmacokinetics of both drugs were unaffected. Co-administration was well tolerated. When transitioning from rivaroxaban to warfarin, INR monitoring during co-administration should be performed at the trough rivaroxaban concentration to minimize the effect of rivaroxaban on INR.

Cardiac recovery and outcome of neonates and infants presenting with severe aortic coarctation and depressed cardiac function.

OBJECTIVES: Coarctation of the aorta represents 5-8% of all congenital heart diseases. Children with severe coarctation of the aorta may present with significant depression of myocardial function. The aim of this study is to identify short and midterm outcomes of neonates and infants with isolated coarctation of the aorta and depressed left ventricular systolic function with regard to recovery of their cardiac function. METHODS: All patients with isolated coarctation of the aorta who underwent surgical repair between December 2002 and December 2015 were retrospectively reviewed in a cohort study. The patients were divided into 2 groups: (1) Patients with depressed left ventricle systolic function who were found to have an ejection fraction and fractional shortening less than 55% and 25%, respectively, (2) Patients with coarctation of the aorta and normal left ventricle systolic function (Control Group). We reviewed both groups after surgery and compared them in terms of their cardiac function recovery. RESULTS: 58 patients were included. 25 patients (43%) depressed left ventricle systolic function group, 33 patients (57%) Control Group. There were statistically significant differences in ejection fraction and fractional shortening (p < 0.0001) between the two groups before surgery. Follow-up demonstrated improvement and recovery of ventricular function in most of the patients, six months after surgery there was no more statistical difference between the groups in terms of cardiac function. CONCLUSION: Majority of the patients with isolated coarctation of the aorta and depressed left ventricle systolic function showed improvement of ventricular function within 4 weeks after surgery, except for patients with residual coarctation of the aorta.

Predictors for the Outcome of Aortic Regurgitation After Cardiac Surgery in Patients with Ventricular Septal Defect and Aortic Cusp Prolapse in Saudi Patients.

BACKGROUND AND AIM: Aortic valve (AV) prolapse and subsequent aortic regurgitation (AR) are two complications of ventricular septal defects (VSD) that are located close to or in direct contact with the AV. This finding is one of the indications for surgical VSD closure even in the absence of symptoms to protect the AV integrity. The goal of our study was to assess the outcome and to identify the predictors for improvement or progression of AR after surgical repair. MATERIALS AND METHODS: A retrospective study of all children with VSD and AV prolapse who underwent cardiac surgery at King Abdulaziz Cardiac Centre in Riyadh between July 1999 and August 2013. RESULTS: A total of 41 consecutive patients, operated for VSD with prolapsed AV, with or without AR, were reviewed. The incidence of AV prolapse in the study population was 6.8% out of 655 patients with VSD. Thirty-six (88%) patients had a perimembranous VSD, and four had doubly committed VSD. Only one patient had an outlet muscular VSD. Right coronary cusp prolapse was found in 38 (92.7%) patients. Preoperative AR was absent in five patients, mild or less in 25 patients, moderate in seven, and severe in four patients. Twenty-six patients showed improvement in the degree of AR after surgery (Group A), 14 patients showed no change in the degree of AR (Group B) while only one patient showed the progression of his AR after surgery. Those with absent AR before surgery remained with no AR after surgery. Improvement was found more in those with mild degree of AR preoperatively compared to those with moderate and severe AR. Female gender also showed a tendency to improve more as compared to male. CONCLUSION: Early surgical closure is advisable for patients with VSD and associated AV prolapse to achieve a better outcome after repair and to prevent progression of AR in future.

Pharmacokinetic and pharmacodynamic characterisation of JNJ-40411813, a positive allosteric modulator of mGluR2, in two randomised, double-blind phase-I studies.

Metabotropic glutamate receptor-2 positive allosteric modulator, JNJ-40411813 (ADX71149), was characterised for clinical effects in healthy volunteers in two phase-1 studies. In study 1, healthy men received 50-, 100-, 150- or 225 mg and women received 100 mg JNJ-40411813 (n=6, each cohort) or placebo (n=2, each cohort) twice daily for seven days; smoking men (n=30) received placebo twice daily on days 1-7, 100 mg JNJ-40411813 (n=20) or placebo (n=10) on days 8-14. In study 2, healthy men received intravenous 0.005 mg/kg S(+) ketamine over 60 min at 3 (n=24; cohort 1), 12 h (n=8; cohort 3), and 24 h (n=8; cohort 2) after a single oral dose of 500 mg JNJ-40411813 or placebo. The pharmacokinetics and effects of JNJ-40411813 on cognition and subjective awareness were evaluated. Plasma JNJ-40411813 exposure was dose-dependent, t max ranged from 3-4 h and t 1/2 19.4-34.2 h across the dose levels. JNJ-40411813 significantly (p=0.02) reduced continuity of attention score (150 mg dose) and ameliorated smoking withdrawal-induced changes in power of attention and quality of episodic memory versus placebo. A modest reduction in alertness was observed at 150-225 mg doses, JNJ-40411813 (500 mg) reduced S(+) ketamine-induced negative symptoms by approximately 43% and 30% in cohorts 1 and 3, respectively. JNJ-40411813 was generally well-tolerated.

Bioequivalence of a darunavir/cobicistat fixed-dose combination tablet versus single agents and food effect in healthy volunteers.

BACKGROUND: Darunavir requires pharmacokinetic enhancement to increase its bioavailability. Cobicistat is potentially an alternative pharmacokinetic booster to ritonavir. Bioequivalence of a darunavir/cobicistat fixed-dose combination (FDC) versus darunavir and cobicistat co-administered as single agents and the effect of a high-fat meal on the pharmacokinetics of the FDC were evaluated. METHODS: In this Phase I, open-label, randomized, three-panel, crossover study (NCT01619527), healthy volunteers received a single dose of darunavir (800 mg) with cobicistat (150 mg) as either an FDC or as single agents co-administered under fasted (panel 1, n=74) or fed (breakfast, panel 2, n=40) conditions, or as the FDC under fasted versus fed (high-fat breakfast) conditions (panel 3, n=19), with a ≥7 day washout period between treatments. Pharmacokinetic profiles, safety and tolerability were assessed. RESULTS: 90% confidence intervals of the least square mean ratios for darunavir and cobicistat maximum plasma concentration and area under the plasma concentration-time curve (AUC) were all within 80.00% and 125.00% in panels 1 and 2. Administration of the FDC with a high-fat breakfast significantly increased darunavir maximum plasma concentration 2.27-fold and AUC 1.63-1.70-fold, whereas cobicistat pharmacokinetics were unaffected. No volunteers discontinued due to adverse events (AEs). All AEs were grade 1 or 2. Overall, 27 (20%) and 26 (20%) volunteers had ≥1 AE at least possibly related to darunavir and cobicistat, respectively. CONCLUSIONS: Bioequivalence of the darunavir/cobicistat 800/150-mg FDC was demonstrated versus darunavir and cobicistat co-administered as single agents under fasted or fed conditions. Food increased darunavir exposure, therefore, darunavir/cobicistat should be administered with food.

Effects of nicotine withdrawal on cognition in a clinical trial setting.

RATIONALE: Smoking withdrawal has been widely established to produce a range of impairments to the quality of several major domains of cognitive function including attention, working memory and episodic memory. OBJECTIVES: This study was conducted to determine the degree to which smoking withdrawal will produce impairments in cognitive function in phase I clinical trials. METHODS: Healthy male volunteers who were housed in a clinical trial facility for 16 days underwent periods of ad libitum smoking and smoking withdrawal. RESULTS: Smoking withdrawal disrupted aspects of attention and episodic verbal recall and recognition. CONCLUSIONS: This study confirms previous work showing cognitive declines in smoking withdrawal and illustrates that such effects occur in ongoing safety and tolerability studies of new medicines and thus require careful consideration for the assessment of cognitive function in such trials as well as the accurate attribution of adverse events to the safety profiles of the medicines.