Denosumab-induced hypocalcemia in patients with osteoporosis: can you know who will get low?

Hypocalcemia was reported at low rates (0.05-1.7%) in denosumab-treated postmenopausal women with osteoporosis. This real-life study shows a 7.4% rate of denosumab-induced hypocalcemia in community-dwelling osteoporotic men and women. Pretreatment serum calcium and creatinine levels are major predictors for this complication. Serum-calcium monitoring may help to identify and prevent severe hypocalcemia. PURPOSE: RCTs have reported a 0.05-1.7% rate of hypocalcemia in denosumab-treated postmenopausal women with osteoporosis, but long-term real-life data are lacking. We assessed the rate of hypocalcemia in osteoporotic community-dwelling patients treated with denosumab. METHODS: A retrospective analysis was conducted based on medical records (2010-2018) from a large HMO. An albumin-adjusted serum calcium concentration lower than 8.5 mg/dL was defined as hypocalcemia. RESULTS: We included 2005 patients (93% women, mean age 76 ± 9 years). Hypocalcemia developed during treatment in 149 patients (7.4%; 1% less than 8 mg/dL): in 66 after 0.5-1 years; 48 after 1-2 years; 35 after > 2 years. On comparison of the hypocalcemic and normocalcemic patients, the strongest predictors of hypocalcemia were pretreatment levels of albumin-adjusted serum calcium (9.1 ± 0.4 vs. 9.4 ± 0.5 mg/dL, respectively; p < 0.05) and creatinine (0.9 ± 0.5 vs. 0.8 ± 0.3 mg/dL, respectively; p < 0.05). The hypocalcemia rate increased in parallel to a decrease in eGFR (p = 0.032 for the difference between eGFR ranges). Baseline calcium level ≤ 9.31 mg/dL predicted hypocalcemia with a sensitivity of 77% and specificity of 56%. A model of (- 2)*calcium + creatinine predicted hypocalcemia (3.7% when lower and 17.1% when higher than - 17.4). Gender, age, 25-hydroxyvitamin-D, parathyroid hormone, alkaline phosphatase, and whether denosumab was given as first or advanced line of osteoporotic therapy had no predictive value. CONCLUSION: Real-life rates of denosumab-induced hypocalcemia are higher than previously reported. Hypocalcemia might develop after each dose of denosumab in ongoing treatment. Adequate calcium and vitamin D supplementation are needed. Serum calcium monitoring is advised in high-risk patients for early detection of severe hypocalcemia.

CATTLE (CAncer treatment treasury with linked evidence): An integrated knowledge base for personalized oncology research and practice.

Despite the existence of various databases cataloging cancer drugs, there is an emerging need to support the development and application of personalized therapies, where an integrated understanding of the clinical factors and drug mechanism of action and its gene targets is necessary. We have developed CATTLE (CAncer Treatment Treasury with Linked Evidence), a comprehensive cancer drug knowledge base providing information across the complete spectrum of the drug life cycle. The CATTLE system collects relevant data from 22 heterogeneous databases, integrates them into a unified model centralized on drugs, and presents comprehensive drug information via an interactive web portal with a download function. A total of 2,323 unique cancer drugs are currently linked to rich information from these databases in CATTLE. Through two use cases, we demonstrate that CATTLE can be used in supporting both research and practice in personalized oncology.

Sub-chronic (13-week) oral toxicity study, preceded by an in utero exposure phase and genotoxicity studies with fish source phosphatidylserine in rats.

The safety of fish phosphatidylserine (PS) conjugated to DHA (InCog™) was examined in a series of toxicology studies as first step to support future use in infants and general population using in vitro genotoxicity tests and in a sub-chronic toxicity study with an in-utero exposure phase. PS is a major lipid in the cell membrane, active in various membrane-mediated processes. PS-DHA, present in human milk, has been suggested to be important for early brain development. Rats were exposed to diets containing 1.5%, 3% or 4.5% InCog or two control diets. Parental (F0) animals were fed throughout mating, gestation and lactation. Subsequently, a subchronic, 13-week study was conducted on the F1 animals followed by 4 weeks of recovery. The genotoxicity tests showed no mutagenicity potential. No significant toxicological findings were found in the F0 rats or the F1 pups. In the 13-weeks study, an increase in the presence of renal minimal-mild multifocal corticomedullary mineralization was noted in nine females of the high-dose group. This change was not associated with any inflammatory or degenerative changes in the kidneys. The no-observed-adverse-effect level (NOAEL) in the present study was placed at 3% in the diet (mid-dose group), equivalent to an overall intake of at least 2.1 g InCog/kg bw/day in the F1 generation.

Treatment outcome of multi-drug resistant tuberculosis in the United Kingdom: retrospective-prospective cohort study from 2004 to 2007.

United Kingdom (UK) guidelines recommend at least 18 months treatment for patients with multidrug-resistant tuberculosis (MDR-TB). Prior to 2008, data on treatment outcome were only available at 12 months and therefore the proportion completing treatment was unknown. This retrospective-prospective cohort study reports on treatment outcomes for MDR-TB patients notified between 2004 and 2007 and examines factors associated with successful outcomes. 70.6% (144/204) completed treatment in 24 months or more, 6.9% (14) stopped treatment, 6.9% (14) died, 7.8% (16) were lost to follow up, 0.5% (1) relapsed and 4.4% (9) were transferred overseas. Following adjustment for age, being non-UK born, non-compliance and having co-morbidities, treatment with a fluoroquinolone (OR 3.09; 95% CI 1.21-7.88; p<0.05) or bacteriostatic drug (OR 4.23; 95% CI 1.60-11.18; p<0.05) were independently associated with successful treatment outcome. Treatment completion for MDR-TB cases remains below the World Health Organization (WHO) target. Our findings support current WHO guidelines for MDR-TB treatment. The UK should consider adopting individualised regimens based on WHO recommended drugs, taking into account drug sensitivities. Improving treatment completion rates will be key to tackling further drug resistance and transmission from untreated infectious cases.

Outcomes among tuberculosis patients with isoniazid resistance in Georgia, 2007-2009.

BACKGROUND: The optimal management strategy for patients with isoniazid (INH) monoresistant forms of tuberculosis (TB) has been widely debated. The current daily 9-month regimen of rifampin, pyrazinamide and ethambutol was established based largely on trials in settings with low TB rates and low rates of drug resistance. OBJECTIVE: To explore the outcomes of patients with INH-monoresistant TB in the country of Georgia, a setting with both high TB rates and drug-resistant forms of the disease. METHODS: Retrospective record review of all patients diagnosed with smear-positive pulmonary TB resistant to either INH or INH+SM (streptomycin) in Georgia between 2007 and 2009. RESULTS: Of 8752 patients with pulmonary TB registered in Georgia, 909 were found to have INH or INH+SM resistance. Treatment outcomes were relatively poor in this group, with only 71% treatment success. Outcomes were significantly worse among patients with older age and a history of previous treatment. CONCLUSIONS: INH or INH+SM resistance in pulmonary TB patients in Georgia is common. The low rates of treatment success suggest the need for an improved treatment regimen for patients with resistance to these first-line drugs; this need is particularly pronounced among the subset of patients with a history of previous treatment.

Initial clinical experience with implantable loop recorders.

The purpose of this study was to review the initial experience of a university hospital with Implantable Loop Recorders (ILR) for diagnosis of recurrent unexplained syncope or presyncope. Twelve patients with syncope or presyncope of unknown etiology (who had a negative tilt table test, electrophysiologic study, and neurologic work-up) underwent implantation of ILR. All implants were performed using the Reveal ILR (Medtronic AVE, Santa Rosa, California). The 8 cc device is 61 mm long, 19 mm wide, 8 mm thick and weighs 17 grams. It has 18 months of battery life and has 2 electrodes with 38.5 mm spacing. The device is nonvascular and is implanted approximately 2 fingerbreadths below the clavicle in a subcutaneous pocket (1.5 inches long) and is secured via polydacron suture to the pre-pectoral fascia/pectoralis muscle. Twelve patients with a mean age of 61 +/- 22 years received the ILR. Ten patients had syncope and 2 had presyncope. Three patients had coronary artery disease and 2 had dilated cardiomyopathy. ILRs were implanted for a mean follow-up period of 7.2 +/- 5.8 months (range, 1 day to 18 months). Two patients still continue to be monitored at the time of this report. The mean number of events prior to ILR was 6.0 +/- 5.4. Eight patients (66%) had recurrent syncope after implantation. One patient was not available for follow-up. There were no significant complications from the implant. In 5/12 patients (42%), the ILR helped to diagnose the etiology of the syncopal episode. Syncope was secondary to asystole in three patients, junctional bradycardia in another patient, and seizure activity in a fifth patient (high-frequency noise recorded on the electrocardiogram during sinus rhythm). The 4 patients with ILR-documented bradyarrhythmias underwent permanent pacemaker implantation and are alive and well. ILR implantation is a simple, useful and safe method in assisting with the diagnosis of recurrent unexplained syncope or presyncope after an inconclusive electrophysiologic and neurologic evaluation.

Increased vascular endothelial growth factor 165 binding to kinase insert domain-containing receptor after infection of human endothelial cells by recombinant adenovirus encoding the Vegf(165) gene.

BACKGROUND: The angiogenic effect of vascular endothelial growth factor (VEGF(165)) is mediated mainly through the high-affinity tyrosine kinase receptor VEGF-R2 (KDR/flk-1). This study examined the effects of VEGF overexpression by primary human endothelial cells (ECs), which do not express VEGF under physiological conditions, on cell proliferation, VEGF binding to the kinase insert domain-containing receptor (KDR), and KDR expression. METHODS AND RESULTS: Human primary ECs and SMCs were infected by recombinant adenoviral vector encoding VEGF(165) (rAdVEGF). Proliferation rate, bromodeoxyuridine incorporation, (125)I-labeled VEGF(165) binding to the KDR receptor, and KDR expression were tested in the infected cells and in cells supplemented with VEGF protein. Enhanced proliferation and a significant increase in (125)I-VEGF(165) binding to the KDR receptor were induced by rAdVEGF infection of ECs (autocrine effect) as well as by addition of recombinant VEGF(165) to noninfected cells. Infection of ECs by rAdVEGF led to posttranscriptional upregulation of the KDR receptor, whereas KDR mRNA expression levels remained unchanged. Similar effects were observed with supplemented recombinant VEGF(165) to noninfected ECs; nevertheless, this phenomenon occurred only with high VEGF(165) concentrations (10 ng/mL). CONCLUSIONS: The effect of VEGF(165) on proliferation and upregulation of KDR receptor expression demonstrated an autocrine phenomenon of EC sensitization. The fact that high concentrations of VEGF may be achieved in vivo by local continuous overexpression of VEGF(165) by gene transfer emphasizes the potential advantage of gene transfer over protein supplementation for therapeutic angiogenesis.

Organization and dynamics of pyrene and pyrene lipids in intact lipid bilayers. Photo-induced charge transfer processes.

The dynamics of fluorescence quenching and the organization of a series of pyrene derivatives anchored in various depths in bilayers of phosphatidylcholine small unilamellar vesicles was studied and compared with their behavior in homogeneous solvent systems. The studies include characterization of the environmental polarity of the pyrene fluorophore based on its vibronic peaks, as well as the interaction with three collisional quenchers: the two membrane-soluble quenchers, diethylaniline and bromobenzene, and the water soluble quencher potassium iodide. The system of diethylaniline-pyrene derivatives in the membrane of phosphatidylcholine vesicles was characterized in detail. The diethylaniline partition coefficient between the lipid bilayers and the buffer is approximately 5,800. Up to a diethylaniline/phospholipid mole ratio of 1:3 the perturbation to membrane structure is minimal so that all photophysical studies were performed below this mole ratio. The quenching reaction, in all cases, was shown to take place in the lipid bilayer interior and the relative quenching efficiencies of the various probe molecules was used to provide information on the distribution of both fluorescent probes and quencher molecules in the lipid bilayer. The quenching efficiency by diethylaniline in the lipid bilayer was found to be essentially independent on the length of the methylene chain of the pyrene moiety. These findings suggest that the quenching process, being a diffusion controlled reaction, is determined by the mobility of the diethylaniline quencher (with an effective diffusion coefficient D approximately 10(-7) cm2 s-1) which appears to be homogeneously distributed throughout the lipid bilayer. The pulsed laser photolysis products of the charge-transfer quenching reaction were examined. No exciplex (excited-complex) formation was observed and the yield of the separated radical ions was shown to be tenfold smaller than in homogenous polar solutions. The decay of the radical ions is considerably faster than the corresponding process in homogenous solutions. Relatively high intersystem crossing yields are observed. The results are explained on the basis of the intrinsic properties of a lipid bilayer, primarily, its rigid spatial organization. It is suggested that such properties favor ion-pair formation over exciplex generation. They also enhance primary geminate recombination of initially formed (solvent-shared) ion pairs. Triplet states are generated via secondary geminate recombination of ion pairs in the membrane interior. The results bear on the general mechanism of electron transfer processes in biomembranes.