Comparing dynamic treatment regimes using repeated‐measures outcomes: modeling considerations in SMART studies

A dynamic treatment regime (DTR) is a sequence of decision rules, each of which recommends a treatment based on a patient's past and current health status. Sequential, multiple assignment, randomized trials (SMARTs) are multi‐stage trial designs that yield data specifically for building effective DTRs. Modeling the marginal mean trajectories of a repeated‐measures outcome arising from a SMART presents challenges, because traditional longitudinal models used for randomized clinical trials do not take into account the unique design features of SMART. We discuss modeling considerations for various forms of SMART designs, emphasizing the importance of considering the timing of repeated measures in relation to the treatment stages in a SMART. For illustration, we use data from three SMART case studies with increasing level of complexity, in autism, child attention deficit hyperactivity disorder, and adult alcoholism. In all three SMARTs, we illustrate how to accommodate the design features along with the timing of the repeated measures when comparing DTRs based on mean trajectories of the repeated‐measures outcome. Copyright © 2015 John Wiley & Sons, Ltd.     

Resolution of recalcitrant chronic papillary conjunctivitis associated with epiphora following punctoplasty and lacrimal stenting

Objective

To assess the use of lacrimal stenting for chronic papillary conjunctivitis associated with epiphora in young adults with little or no atopic background.

Plasma leptin and the cholesterol saturation of bile are correlated in obese women after weight loss

Increased cholesterol secretion is a major alteration of biliary function in obese subjects Leptin is a regulator of food intake and is increased in plasma of subjects with low energy expenditure and high adiposity. We investigated the relationship between leptin and the cholesterol saturation of bile in obese women before and after weight reduction by energy restriction (5.02 MJ/d). We studied women (n = 14) with a body mass index (BMI) > or = 30 kg/m(2) who were 35.4 +/- 2.3 y old and who did not have a history of gallstones. They were studied by ultrasound to ensure absence of stones or sludge. BMI, gallbladder bile composition, plasma leptin, serum lipids and lipoproteins cholesterol levels were recorded at baseline and after 6 wk of weight reduction. There were decreases in BMI (33.9 +/- 3.1 to 31.1 +/- 3.6 kg/m(2), P < 0.0001) and leptin levels (16.7 +/- 9.7 to 10.0 +/- 6.7 micro mol/L, P < 0.05) during weight loss. After the experimental period, there were positive correlations between plasma leptin levels and BMI (r = 0.71, P < 0.004); leptin levels and the cholesterol saturation index (CSI) (r = 0.53, P < 0.05); the CSI and LDL cholesterol (r = 0.73, P < 0.003); and negative correlations between leptin levels and HDL cholesterol (r = -0.54, P < 0.05) and LDL cholesterol (r = -0.57, P < 0.03). We have shown relationships among HDL cholesterol, CSI and leptin. This could be useful in understanding the pathophysiology of cholesterol gallstone formation in obese people.     

Parathyroid adenomas evaluated by Tl-201/Tc-99m pertechnetate subtraction scintigraphy and high-resolution ultrasonography

Thallium-201/technetium-99m pertechnetate subtraction scintigraphy of the parathyroid glands was performed in a prospective study of 33 patients who had undergone bilateral neck exploration for elevated serum calcium and serum parathyroid hormone levels. In 31 cases, the Tl-201/Tc-99m subtraction technique yielded an overall sensitivity of 81%, specificity of 99%, and accuracy of 94% for identifying solitary parathyroid adenomas. Tl-201/Tc-99m subtraction scintigraphy correctly identified 73% of parathyroid adenomas weighing less than 499 mg, 79% of those weighing 500-1,499 mg, and 100% of adenomas weighing more than 1,500 mg. In a subgroup of 24 patients with solitary parathyroid adenomas who underwent both scintigraphy and high-resolution sonography, the sensitivity, specificity, and accuracy of both procedures were similar.     

Adenosine 5'-O-(1-boranotriphosphate) derivatives as novel P2Y(1) receptor agonists

P2-receptors (P2-Rs) represent important targets for novel drug development. Most ATP analogues proposed as potential drug candidates have shortcomings such as limited receptor-selectivity and limited stability that justify the search for new P2-R agonists. Therefore, a novel series of nucleotides based on the adenosine 5'-O-(1-boranotriphosphate) (ATP-alpha-B) scaffold was developed and tested as P2Y(1)-R agonists. An efficient four-step one-pot synthesis of several ATP-alpha-B analogues from the corresponding nucleosides was developed, as well as a facile method for the separation of the diastereoisomers (A and B isomers) of the chiral products. The potency of the new analogues as P2Y(1)-R agonists was evaluated by the agonist-induced Ca2+ release of HEK 293 cells stably transfected with rat-brain P2Y(1)-R. ATP-alpha-B A isomer was equipotent with ATP (EC50 = 2 x 10(-7) M). However, 2-MeS- and 2-Cl- substitutions on ATP-alpha-B (A isomer) increased the potency of the agonist up to 100-fold, with EC50 values of 4.5 x 10(-9) and 3.6 x 10(-9) M, compared to that of the ATP-alpha-B (A isomer). Diastereoisomers A of all ATP-alpha-B analogues were more potent in inducing Ca2+ release than the corresponding B counterparts, with a 20-fold difference for 2-MeS-ATP-alpha-B analogues. The chemical stability of the new P2Y(1)-R agonists was evaluated by 31P NMR under physiological and gastric-juice pH values at 37 degrees C, with rates of hydrolysis of 2-MeS-ATP-alpha-B of 1.38 x 10(-7) s-1 (t1/2 of 1395 h) and 3.24 x 10(-5) s-1 (t1/2 = 5.9 h), respectively. The enzymatic stability of the new analogues toward spleen NTPDase was evaluated. Most of the new analogues were poor substrates for the NTPDase, with ATP-alpha-B (A isomer) hydrolysis being 5% of the hydrolysis rate of ATP. Diastereoisomers A and B exhibited different stability, with A isomers being significantly more stable, up to 9-fold. Furthermore, A isomers that are potent P2Y(1)-R agonists barely interact with NTPDase, thus exhibiting protein selectivity. Therefore, on the basis of our findings, the new, highly water-soluble, P2Y(1)-R agonists may be considered as potentially promising drug candidates.     

Atypical paraneoplastic myasthenic syndrome: Lambert-Eaton syndrome or myasthenia?]

We report a case of paraneoplastic myasthenic syndrome with clinical features suggesting Lambert Eaton syndrome but without the electromyographic elements required for diagnosis. Anti-calcium channel antibodies were also lacking. The electromyogram evidenced a block and the Tensilon test was positive. The efficacy of anticholinesterases argued in favor of myasthenia but anti-acetylcholine receptor antibodies were negative. The block was more of a mixed nature, involving both presynaptic transmission as in Lambert Eaton syndrome and post-synaptic transmission as in paraneoplastic myasthenia. The primary tumor was identified as a small-cell neuroendocrine lung carcinoma on mediastinal biopsies obtained directly on CT-scan guided puncture of a mediastinal node. Thoracotomy was thus avoided. The Lambert Eaton syndrome is a paraneoplastic manifestation of small-cell lung cancer in 50% of the cases unlike generalized myasthenia which apparently is never associated with small-cell lung cancer. A mixed paraneoplastic neuro-muscle junction disorder with aspects of each can be exceptionally observed.     

Isolated rib fractures in elderly patients: mortality and morbidity.

OBJECTIVES: To describe the management, morbidity and mortality seen with isolated rib fractures in elderly patients and assess the need for hospitalization. DESIGN: A case series. SETTING: A tertiary care centre in Tel Aviv. METHODS: Hospital records of 77 elderly patients (age 65 yr and older) admitted with isolated rib fractures were reviewed over a 9-year period. Main outcome measures: Demographic, medical and hospitalization data, blood hemoglobin and oxygen saturation levels. RESULTS: The number of fractured ribs was found to correlate with the morbidity (p = 0.027) and mortality (p = 0.006). There were no significant differences in these rates with respect to comorbidity except for diabetes (higher morbidity) and congestive heart failure (higher mortality). Twenty-eight patients (36%) had pulmonary complications and 1 had cardiac complications. Pulmonary complications were fatal in 6 patients (7.8%). Multivariate analysis of the factors related to morbidity demonstrated that only oxygen saturation (p = 0.0009) and diabetes (p = 0.03) correlated significantly. CONCLUSIONS: In spite of significant morbidity and mortality in elderly patients with isolated rib fractures, prediction of the prognosis for these patients is presently not possible. Admission for observation and treatment is therefore justified and beneficial.