Effectiveness of Tiotropium/Olodaterol in the Real World: A Post Hoc Subgroup Analysis After the First Year of Use.

INTRODUCTION: Real-world evidence is needed to optimize pharmacotherapy for chronic obstructive pulmonary disease (COPD). The effectiveness of inhaled tiotropium/olodaterol according to baseline symptoms and previous COPD treatment and predictors of response were assessed. METHODS: This was a post hoc analysis of a 52-week post-marketing surveillance study of tiotropium/olodaterol in 1255 Japanese patients with COPD of all severities. We analyzed change in total COPD Assessment Test (CAT) score and lung function (forced expiratory volume in 1 s [FEV1] and forced vital capacity [FVC]). Patient subgroups were analyzed based on baseline CAT score (< 10 [n = 184], ≥ 10 [n = 507]) and previous COPD treatment (treatment-naive [n = 407], previously treated [n = 848], treatment with long-acting muscarinic antagonist monotherapy [n = 161]). RESULTS: In the CAT ≥ 10 subgroup, tiotropium/olodaterol showed statistically significant improvements in mean total CAT score (- 6.2; 95% confidence interval [CI] - 7.2, - 5.1), FEV1 (0.109 L; 95% CI 0.059, 0.159) and FVC (0.171 L; 95% CI 0.096, 0.245), which continued through Week 52. CAT score and lung function improvement were greatest in treatment-naive patients: - 7.6 (95% CI - 9.2, - 6.1) mean total CAT score, 0.177 L (95% CI 0.076, 0.279) mean FEV1 and 0.178 L (95% CI 0.036, 0.319) mean FVC. Baseline factors associated with treatment response (total CAT score improvement ≥ 2 points) were: shorter COPD duration (odds ratio [OR] 0.91; 95% CI 0.87, 0.96), total CAT score ≥ 10 (OR 3.86; 95% CI 2.46, 6.06) and treatment-naive status (OR 1.86; 95% CI 1.12, 3.07). Baseline total CAT scores ≥ 13 predicted responses to tiotropium/olodaterol in all previous COPD treatment subgroups including treatment-naive patients. CONCLUSIONS: Tiotropium/olodaterol improved symptoms and lung function in Japanese COPD patients. Our results support the possible use of tiotropium/olodaterol in treatment-naive patients and those with total CAT scores ≥ 10. TRAIL REGISTRATION: Clinicaltrials.gov Identifier for parent study: NCT02850978.

OPA1 mutations in Japanese patients suspected to have autosomal dominant optic atrophy.

PURPOSE: To report three types of heterozygous mutations in the OPA1 gene in five patients from three families with autosomal dominant optic atrophy (ADOA, MIM#165500). METHODS: DNA was extracted from the leukocytes of the peripheral blood. For mtDNA, mutations were examined at positions 11778, 3460 and 14484. For the OPA1 gene, the exons were amplified by PCR and mutations were detected by restriction enzymes or the dye terminator method. RESULTS: We detected three types of OPA1 mutation but no mtDNA mutations. In the OPA1 gene, heterozygous frameshift mutations from codon 903 due to a four-base pair deletion in exon 27 were detected in three patients from one family (c.2708_2711delTTAG, p.V903GfsX905). A heterozygous mutation due to a three-base pair deletion in exon 17, leading to a one-amino acid deletion (c.1618_1620delACT, p.T540del), and a heterozygous mutation due to a one-base substitution in exon 11, leading to a stop codon (c.1084G>T, p.E362X), were detected in sporadic cases. CONCLUSION: OPA1 mutations existed in three Japanese families with ADOA. After a detailed clinical assessment of the proband, the screening of the OPA1 gene may be helpful for precise diagnosis of ADOA, provided the relevant information of the family members is limited.

SigC, the group 2 sigma factor of RNA polymerase, contributes to the late-stage gene expression and nitrogen promoter recognition in the cyanobacterium Synechocystis sp. strain PCC 6803.

We examined the role of SigC (Sll0184), a sigma factor of RNA polymerase (RNAP), in a unicellular cyanobacterium, Synechocystis sp. strain PCC 6803. On the inactivation of sigC, which is an Escherichia coli rpoD homolog, cells were viable but had a low survival rate in the stationary phase of growth under normal physiological conditions, indicating that SigC is a group 2 type sigma factor. In analyses of transcript and protein levels using the sigC knockout strain, it was found that expression of glnB, a nitrogen key regulatory gene, is controlled by SigC in the stationary phase. Primer extension revealed that the glnB nitrogen promoter (P2) was specifically recognized by SigC in the stationary phase under conditions of nitrogen starvation. In vitro studies with purified enzymes indicated effective transcription, on supercoiled DNA templates, from P2 by SigC-RNAP with NtcA which is an activator for nitrogen gene transcription. DNase I footprinting also indicated binding and related sites of NtcA and/or RNAP with SigC on the nitrogen promoter. The unique promoter architecture and the mechanism of transcription by RNAP with SigC are also discussed.