The impact of oocyte death on mouse primordial follicle formation and ovarian reserve.

Background: Ovaries, the source of oocytes, maintain the numbers of primordial follicles, develop oocytes for fertilization and embryonic development. Although it is well known that about two-thirds of oocytes are lost during the formation of primordial follicles through cyst fragmentation and the aggregation of oocytes within the cyst, the mechanism responsible for this remains unclear. Methods: We provide an overview of cell death that is associated with the oocyte cyst breakdown and primordial follicle assembly along with our recent findings for mice that had been treated with a TNFα ligand inhibitor. Main Findings: It is generally accepted that apoptosis is the major mechanism responsible for the depletion of germ cells. In fact, a gene deficiency or the overexpression of apoptosis regulators can have a great effect on follicle numbers and/or fertility. Apoptosis, however, may not be the only cause of the large-scale oocyte attrition during oocyte cyst breakdown, and other mechanisms, such as aggregation, may also be involved in this process. Conclusion: The continued study of oocyte death during primordial follicle formation could lead to the development of novel strategies for manipulating the primordial follicle pool, leading to improved fertility by enhancing the ovarian reserve.

Retention of higher fertility depending on ovarian follicle reserve in cystine-glutamate transporter gene-deficient mice.

The cystine-glutamate transporter (xCT) is responsible for the transport of cystine into cells. We recently found that xCT-deficient (xCTKO) aged mice maintained a higher rate of ovulation and ovarian weight compared with wild-type (WT) mice. It has been reported that a xCT deficiency in cultured cells induces autophagy through the suppression of mTOR survival pathways. We have previously reported that starvation in neonatal mice increases the number of primordial follicles with concomitant autophagy activation. Therefore, we investigated age-related changes in follicle reserve and fertility in xCTKO mice and clarified whether the PI3K/AKT/mTOR signaling pathway contributes to this. The numbers of offspring in the xCTKO mice aged 10 and 12 months were significantly higher than those in the WT mice. The primordial follicle numbers in xCTKO neonatal mice tended to be higher than WT mice during all times evaluated. In contrast, the primary follicle number was significantly lower in the xCTKO mice at 60 h after birth. The expression of p-AKT, which promotes follicle development, was significantly lower in xCTKO mice than that in WT mice, whereas the expression ratios of LC3-II/LC3-I were significantly higher. The xCTKO mice had significantly more primordial follicles than WT mice at 2 months of age and showed a similar trend at 13-15 months of age. These results suggest that the maintenance of fertility in aged xCTKO mice can be attributed to high follicle reserve after puberty by suppression of follicle activation during the neonatal period.

An ectopic thymoma arising in the middle mediastinum that was difficult to distinguish from a lymph node metastasis.

BACKGROUND: Ectopic thymomas often occur in the upper mediastinum; however, they rarely arise in the middle mediastinum, especially on the dorsal side of the innominate vein and superior vena cava in the peribronchial region. CASE PRESENTATION: Six years prior, a 27-year-old female presented to our department and was diagnosed with locally advanced left breast cancer. First, we administered chemotherapy including an anti-human epidermal growth factor receptor 2 antibody. The size of the tumor was markedly reduced, and a radical operation involving mastectomy and axillary lymph node dissection was then performed. The patient underwent radiotherapy after the mastectomy, followed by trastuzumab therapy; she continued to receive endocrine therapy thereafter. She underwent computed tomography once a year after the surgery, and a nodule in the middle mediastinum on the dorsal side of the innominate vein and superior vena cava in the parabronchial region was detected at 4 years. We speculated that the nodule was a solitary mediastinal lymph node metastasis from her breast cancer; therefore, we performed thoracoscopic resection of the tumor. We diagnosed the tumor as a thymoma. Currently, the patient visits our hospital to receive continuous hormone therapy for her breast cancer, and the latest computed tomography scan demonstrated no metastases from or recurrence of her breast cancer or thymoma. CONCLUSIONS: We report a case of ectopic thymoma in the middle mediastinum. The tumor, which was detected during systemic therapy for locally advanced breast cancer, was located on the dorsal side of the innominate vein and superior vena cava in the parabronchial region and was indistinguishable from a lymph node metastasis from breast cancer.

Feasibility of autologous fibrin glue in general thoracic surgery.

BACKGROUND: Fibrin glue effectively controls air leakage in lung surgery; however, allogenic fibrin glue cannot eliminate the risks of infection and allergy despite current sterilization methods. Autologous fibrin glue (AFG) could be a good alternative, but is not commonly used worldwide because of its limited availability and lack of evidence. Herein, we report clinical outcomes of AFG in thoracic surgery. METHODS: We retrospectively analyzed patients who underwent lobectomies or segmentectomies between November 2016 and September 2017 in our institution. We used two types of AFGs. One was a partially-autologous fibrin glue (PAFG), the components of which are largely autologous but which contains allogenic thrombin. The other was a completely-autologous fibrin glue (CAFG) which has no allogenic components. PAFG was used in the first half of the study period, after which CAFG was used from March 2017 onward. Patients who did not undergo AFG generation were categorized as the non-AFG group. The perioperative outcomes of the three groups were evaluated. RESULTS: A total of 207 patients underwent lung surgery, including 118 lobectomies and 89 segmentectomies. Among them, 83 patients received PAFG, 94 received CAFG, and 30 received non-AFG. The mean postoperative drainage period was within a few days in each group (PAFG vs. CAFG vs. non-AFG: 3.23±3.91 vs. 3.16±4.04 vs. 3.17±4.16 days, respectively; P=0.405), and the incidence of postoperative prolonged air leakage was within an acceptable range (PAFG vs. CAFG vs. non-AFG: 13.3% vs. 12.8% vs. 16.7%, respectively; P=0.821). CONCLUSIONS: The use of AFG is clinically feasible for patients who undergo lobectomies or segmentectomies. AFGs could be a viable alternative to conventional allogenic fibrin glues.

Activation of autophagy in early neonatal mice increases primordial follicle number and improves lifelong fertility†.

The number of stockpiled primordial follicles is thought to be responsible for the fate of female fertility and reproductive lifetime. We previously reported that starvation in nonsuckling early neonatal mice increases the number of primordial follicles with concomitant autophagy activation, suggesting that autophagy may accelerate the formation of primordial follicles. In this study, we attempted to upregulate the numbers of primordial follicles by administering an autophagy inducer and evaluated the progress of primordial follicle formation and their fertility during the life of the mice. To induce autophagy, mice were intraperitoneally injected with the Tat-beclin1 D-11 peptide (0.02 mg/g body weight) at 6-54 h or 60-84 h after birth. In animals that received Tat-beclin 1 D-11 by 54 h after birth, the primordial follicle numbers were significantly increased compared with the control group at 60 h. The ratio of expressed LC3-II/LC3-I proteins was also significantly greater. The numbers of littermates from pregnant females that had been treated with Tat-beclin 1 D-11 were maintained at remarkably greater levels until 10 months old. These results were supported by an abundance of primordial follicles at even 13-15 months old.

Ascorbic acid and CoQ10 ameliorate the reproductive ability of superoxide dismutase 1-deficient female mice†.

Superoxide dismutase 1 suppresses oxidative stress within cells by decreasing the levels of superoxide anions. A dysfunction of the ovary and/or an aberrant production of sex hormones are suspected causes for infertility in superoxide dismutase 1-knockout mice. We report on attempts to rescue the infertility in female knockout mice by providing two antioxidants, ascorbic acid and/or coenzyme Q10, as supplements in the drinking water of the knockout mice after weaning and on an investigation of their reproductive ability. On the first parturition, 80% of the untreated knockout mice produced smaller litter sizes compared with wild-type mice (average 2.8 vs 7.3 pups/mouse), and supplementing with these antioxidants failed to improve these litter sizes. However, in the second parturition of the knockout mice, the parturition rate was increased from 18% to 44-75% as the result of the administration of antioxidants. While plasma levels of progesterone at 7.5 days of pregnancy were essentially the same between the wild-type and knockout mice and were not changed by the supplementation of these antioxidants, sizes of corpus luteum cells, which were smaller in the knockout mouse ovaries after the first parturition, were significantly ameliorated in the knockout mouse with the administration of the antioxidants. Moreover, the impaired vasculogenesis in uterus/placenta was also improved by ascorbic acid supplementation. We thus conclude that ascorbic acid and/or coenzyme Q10 are involved in maintaining ovarian and uterus/placenta homeostasis against insults that are augmented during pregnancy and that their use might have positive effects in terms of improving female fertility.

A heterozygous deficiency in protein phosphatase Ppm1b results in an altered ovulation number in mice.

Ppm1b, a metal­dependent serine/threonine protein phosphatase, catalyzes the dephosphorylation of a variety of phosphorylated proteins. Ppm1b­/­ mouse embryos die at the fertilized oocyte stage, whereas Ppm1b+/­ mice with a C57BL/6 background exhibit no phenotypic abnormalities. Because the C57BL/6 strain produces a limited number of pups, in an attempt to produce Ppm1b­/­ mice, congenic Ppm1b+/­ mice with an ICR background were established, which are more fertile and gave birth to more pups. As a result, however, no Ppm1b­/­ offspring were obtained when pairs of Ppm1b+/­ ICR mice were bred again. Ppm1b+/­ male and female ICR mice were analyzed from the viewpoint of fecundity. The Ppm1b haploinsufficiency had no effect on testicular weight or the number of sperm in male mice. Despite the fact that the levels of Ppm1b protein in the ovaries of sexually mature Ppm1b+/­ mice were decreased compared with those of Ppm1b+/+ mice, there appeared to be no significant difference in the histological appearance of the ovaries, litter sizes or plasma progesterone levels at the estrous stage. When superovulation was induced by stimulation using a hormone treatment, the number of ovulated oocytes were the same for Ppm1b+/­ and Ppm1b+/+ mice at 4 weeks of age when the estrous cycle did not proceed, however, the number of ovulated oocytes was lower in sexually mature Ppm1b+/­ mice at 11 weeks of age compared with Ppm1b+/+ mice in the first and the second superovulation cycles. These collective results suggest that follicle development is excessive in Ppm1b+/­ mice, and that this leads to a partial depletion of matured follicles and a corresponding decrease in the number of ovulated oocytes.

Simultaneous three-port thoracoscopic surgery for bilateral lung cancers with a pulmonary vein anomaly: A case report.

INTRODUCTION: Simultaneous resection of bilateral lung cancers is technically challenging but may be preferable to a staged procedure in patients with a partial anomalous pulmonary venous connection (PAPVC) in an affected lobe. We performed single-stage resection of bilateral lung cancers in a patient with a PAPVC. PRESENTATION OF CASE: A 73-year-old man was diagnosed as having bilateral lung cancers (right, cT3N1M0, stage IIIA and left, cT2aN0M0, stage IB). Left upper trisegmentectomy was performed, followed by right upper lobectomy with deep wedge bronchoplasty. A PAPVC was found incidentally in the affected right upper lobe and successfully divided. The postoperative course was uneventful and he commenced chemoradiotherapy. DISCUSSION: Resection of the PAPVC, which was located in the same lobe as the lung cancer, would have mitigated load increase in the right heart and may have alleviated the adverse effects of bilateral lung resection. Moreover, the single-stage procedure likely shortened the overall duration of treatment. CONCLUSION: Single-stage bilateral thoracoscopic resection may have advantages over staged procedures in some patients with PAPVCs.

Non-suckling starvation of neonatal mice promotes primordial follicle formation with activation of ovarian autophagy.

Around the time of oocyte meiotic arrest, germ cell nest breakdown occurs, and primordial follicle (PF) formation is initiated at the perinatal stage. Recently, autophagy was implicated in this process. Autophagy is induced by nutrient starvation. This study was conducted to understand how starvation affects PF formation and autophagy induction during neonatal life. Suckling of neonatal female mice was blocked immediately after birth for 12-36 h to induce starvation. The numbers of PFs at each stage were subsequently counted from serial sections of ovaries. The expression of autophagy-related proteins was also evaluated. The number of PFs peaked at 60 h after birth in the control group. The numbers for the starvation groups were significantly higher than those for the control groups at 12 and 36 h. LC3B was clearly present in the oocyte cytoplasm. At 36 h after birth, the starvation group showed a higher rate of LC3II/LC3-I expression as a marker for autophagy. Moreover, the expression of p62 as a selective substrate for autophagy decreased compared to the control group. The expression of caspase-9 as a marker for apoptosis tended to be lower at 36 h in the starvation groups. These results indicate that starvation promotes PF formation with a concomitant activation of autophagy in early neonatal ovaries, suggesting that autophagy induction during follicle assembly might increase the number of PFs.

Decreased reproductive performance in xCT-knockout male mice.

Sulphoxidation occurs in protamines that are enriched in cysteine and supplies chromatin for packaging. The extracellular fluid contains higher levels of oxidised cysteine (cystine), and some cells utilise system xc-, a cystine transporter in which xCT is the main protein component, to fulfil the need for cysteine. We hypothesised that system xc- might ensure the supply of cysteine needed for spermatogenesis. The reproductive ability of xCT-/- male mice at 6- to 18-weeks of age appeared to be lower than xCT+/+ male mice. The courtship behaviour of the xCT-/- male mice was undynamic, which appeared to be associated with the low reproductive ability of xCT-/- male mice. xCT was found to be expressed in mouse testes, notably in Sertoli cells, as well as in the epididymis and the levels were increased at the time of sexual maturation. Despite the normal histological appearance of testicular tissues, the cauda epididymis of xCT-/- mice contained round, greater numbers of immature spermatogenic cells than that of xCT+/+ mice. However, there were no significant differences in the numbers of sperm stored in the cauda epididymis or in the concentrations of cysteine or glutathione in the testes. The resulting sperm had normal fertilising ability. Thus, system xc- appears to function as a backup system for supplying cysteine to testes and play a pivotal role in supplying cysteine for normal sexual behaviour by a mechanism that is different from that for the supply of cysteine in spermatogenesis.

Measurement of spontaneous blinks in patients with Parkinson's disease using a new high-speed blink analysis system.

INTRODUCTION: Parkinson's disease (PD) patients often have a blinking abnormality. In this study, we examined the kinematic features of spontaneous blinking in 65 PD patients and 62 healthy controls by a new research method utilizing an intelligent vision sensor camera prototype with a 1kHz sampling rate. METHODS: Spontaneous blinks were measured by use of a non-stress 'intelligent vision sensor' camera prototype. RESULTS: The mean spontaneous blink rate was 17.9 (blinks/min) in the PD patients and 15.6 in the controls (no correlation). However, there were extremely low and extremely high blink-rate groups among the PD patients. The amplitude of the closing and opening phase in the PD patients were significantly smaller than those in the controls. Small blink waves (100-200msec) prior to blink onset existed in 60% of the PD patients and in 18% of the controls. CONCLUSION: During spontaneous blinking the blink amplitude is decreased, and the pause between the closing and opening phase is prolonged in patients with PD. Small blink waves prior to blink onset were also characteristically found in the PD patients.

Pulmonary Neoplasms in Patients with Birt-Hogg-Dubé Syndrome: Histopathological Features and Genetic and Somatic Events.

Birt-Hogg-Dubé syndrome (BHD) is an inherited disorder caused by genetic mutations in the folliculin (FLCN) gene. Individuals with BHD have multiple pulmonary cysts and are at a high risk for developing renal cell carcinomas (RCCs). Currently, little information is available about whether pulmonary cysts are absolutely benign or if the lungs are at an increased risk for developing neoplasms. Herein, we describe 14 pulmonary neoplastic lesions in 7 patients with BHD. All patients were confirmed to have germline FLCN mutations. Neoplasm histologies included adenocarcinoma in situ (n = 2), minimally invasive adenocarcinoma (n = 1), papillary adenocarcinoma (n = 1), micropapillary adenocarcinoma (n = 1), atypical adenomatous hyperplasia (n = 8), and micronodular pneumocyte hyperplasia (MPH)-like lesion (n = 1). Five of the six adenocarcinoma/MPH-like lesions (83.3%) demonstrated a loss of heterozygosity (LOH) of FLCN. All of these lesions lacked mutant alleles and preserved wild-type alleles. Three invasive adenocarcinomas possessed additional somatic events: 2 had a somatic mutation in the epidermal growth factor receptor gene (EGFR) and another had a somatic mutation in KRAS. Immunohistochemical analysis revealed that most of the lesions were immunostained for phospho-mammalian target of rapamycin (p-mTOR) and phospho-S6. Collective data indicated that pulmonary neoplasms of peripheral adenocarcinomatous lineage in BHD patients frequently exhibit LOH of FLCN with mTOR pathway signaling. Additional driver gene mutations were detected only in invasive cases, suggesting that FLCN LOH may be an underlying abnormality that cooperates with major driver gene mutations in the progression of pulmonary adenocarcinomas in BHD patients.

Long-term tear volume changes after blepharoptosis surgery and blepharoplasty.

PURPOSE: To evaluate long-term changes in tear volume by using video meniscometry following blepharoptosis surgery and upper blepharoplasty. METHODS: Forty-three eyes of 27 patients with blepharoptosis and 29 eyes of 18 patients with dermatochalasis without lacrimal duct obstruction or other eyelid diseases underwent anterior approach levator advancement or blepharoplasty. Tear volume was evaluated by measurement of tear meniscus radius (R), using video meniscometry preoperatively and at 1.5, 3, and 6 months postoperatively. Margin reflex distance-1 (MRD-1) was measured before and after surgery by using photographs. RESULTS: After blepharoptosis surgery, the mean MRD-1 was significantly increased: 0.45 mm preoperatively, 3.64 mm at 1.5 months, 3.56 mm at 3 months, and 3.57 at 6 months postoperatively (P < 0.001), and the average R value was significantly decreased: 0.29 mm preoperatively, 0.22 mm at 1.5 months, 0.23 mm at 3months, and 0.24 mm at 6 months postoperatively (P < 0.05). Preoperative R was significantly correlated to the reduction rate of R (ΔR). A higher preoperative R was more likely to be decreased (P < 0.01). Postoperative MRD-1 and change in MRD-1 were not correlated to ΔR. After blepharoplasty, the preoperative mean MRD-1 (3.11 mm) was significantly decreased at 1.5 months (2.47 mm; P < 0.01) and 3 months (2.71 mm; P < 0.05) but recovered at 6 months (3.14 mm). However, the average R was not changed: 0.31 mm preoperatively, 0.34 mm at 1.5 months, 0.31 mm at 3 months, and 0.33 mm at 6 months postoperatively. CONCLUSIONS: Long-term tear volume was not changed after blepharoplasty but was decreased after blepharoptosis surgery, and even more so in cases with an initial high tear volume.

Three cases of mesalazine-induced pneumonitis with eosinophilia.

Oral mesalazine, or 5-aminosalicylate, is one of the first-choice medications for the treatment of ulcerative colitis and is commonly used for both induction and maintenance therapy. In a 6-month period, we treated three cases of mesalazine-induced pneumonitis. In all three cases, computed tomography images revealed upper lobe dominant bilateral peripherally localized consolidations. Such images are commonly observed in patients with cryptogenic organizing pneumonia or chronic eosinophilic pneumonia. Computed tomography images for mesalazine-induced pneumonitis have been rarely reported in the literature.

Oxidative stress and redox regulation of gametogenesis, fertilization, and embryonic development.

Oxidative stress caused by elevated reactive oxygen species (ROS) is one of the predominant causes of both male and female infertility. Oxidative stress conditions cause either cell death or senescence by oxidation of cellular molecules including nucleic acid, proteins, and lipids. It is particularly important to minimize oxidative stress when in vitro fertilization is performed for the purpose of assisted reproduction. The problems associated with assisted reproductive technology are becoming evident, and it is now the time to clarify its mechanisms and cope with them. On the other hand, the beneficial roles of ROS, such as intracellular signaling, have become evident. The antithetical functions of ROS make it more difficult to overcome the problems caused by oxidative stress. Despite the difficulty in understanding mammalian reproduction, the mechanisms and problems can be gradually unveiled by advanced technology such as genetic modification of animals.

Small, moderate, and large changes, and the minimum clinically important difference in the University of California, San Diego Shortness of Breath Questionnaire.

Minimum clinically important change of 5 points in the University of California, San Diego Shortness of Breath Questionnaire (SOBQ) is established, but cutoff values between a small, a moderate, and a large change are still unknown. We used the data set of National Emphysema Treatment Trial consisting of severe and very severe chronic obstructive pulmonary disease patients, whose mean age was 64 years. Changes from baseline to post-surgical 6-month follow-up were evaluated. The St. George's Respiratory Questionnaire was used as anchor: |∆SGRQ| < 4, meaningless change; 4 ≤ |∆SGRQ| < 8, small change; 8 ≤ |∆SGRQ| < 13, moderate change; 13 ≤ |∆SGRQ|, large change. We decided the final cutoff values for the SOBQ as medians of the three anchor methods. We also decided the range of cutoff values as the range of three values. In a cohort of surgically treated patients (N = 484), we propose value of 5 (range 5-6), 11 (range 9-15), and 16 (range 14-20) for the cutoff values between a meaningless and a small change (minimum clinically important difference), a small and a moderate change, and a moderate and a large change, respectively. In a cohort of medically treated patients, numbers of patients categorized according to ∆SOBQ scores were similar to those of the patients categorizes according to the ∆SGRQ (N = 480) or ∆Forced expiratory volume in 1 second (N = 425). We propose group-level cutoff values and range between a small, a moderate, and a large changes.

Short-term changes in tear volume after blepharoptosis repair.

PURPOSE: The aim was to evaluate tear volume change by using videomeniscometry before and after blepharoptosis surgery. METHODS: Fifty-nine eyes of 36 patients with blepharoptosis without lacrimal duct obstruction or other eyelid diseases were examined. All the patients underwent levator advancement, and the tear volume was evaluated preoperatively and 1.5 months postoperatively. The margin reflex distance-1 was determined from photographs, and the tear volume was determined by the measurement of tear meniscus radius using videomeniscometry. RESULTS: The mean margin reflex distance-1 was significantly increased after performing a blepharoptosis surgery (0.13 ± 1.13 mm preoperatively vs. 3.18 ± 0.85 mm postoperatively, P < 0.001). The average tear meniscus radius was significantly decreased (0.31 ± 0.16 mm preoperatively vs. 0.23 ± 0.08 mm postoperatively, P < 0.001). A postoperative reduction in the tear meniscus radius was noted in 46 eyes (78%) of 31 patients, and no reduction was noted in 13 eyes (22%) of 12 patients. Preoperative higher tear meniscus radius values were more likely to be decreased (P < 0.01). CONCLUSIONS: The tear volume was decreased after the blepharoptosis surgery was performed, especially for an initially high tear volume.

[Acute encephalitis presenting with symmetrical involvement of the bilateral basal ganglia].

A 8-year-old girl was hospitalized with consciousness disturbance and involuntary movements five days after the onset of fever. Cranial MRI revealed symmetrical involvement of the bilateral basal ganglia with elevated ADC mapping, suggesting vasogenic edema.Her clinical symptoms improved with methylprednisolone pulse therapy without neurological sequelae. The rapid antigen test for group A beta-hemolytic streptococcus was positive and serum ASO was elevated. Myelin basic protein in cerebrospinal fluid was elevated. We suggest that the pathophysiological mechanism in the present case was not necrotic/cytotoxic but autoimmune inflammation, which is compatible with acute disseminated encephalomyelitis associated with streptococcal infection.

Sensitivity and specificity of the Streptococcus pneumoniae urinary antigen test for unconcentrated urine from adult patients with pneumonia: a meta-analysis.

Studies on the sensitivity and specificity of the Binax Now Streptococcus pneumonia urinary antigen test (index test) show considerable variance of results. Those written in English provided sufficient original data to evaluate the sensitivity and specificity of the index test using unconcentrated urine to identify S. pneumoniae infection in adults with pneumonia. Reference tests were conducted with at least one culture and/or smear. We estimated sensitivity and two specificities. One was the specificity evaluated using only patients with pneumonia of identified other aetiologies ('specificity (other)'). The other was the specificity evaluated based on both patients with pneumonia of unknown aetiology and those with pneumonia of other aetiologies ('specificity (unknown and other)') using a fixed model for meta-analysis. We found 10 articles involving 2315 patients. The analysis of 10 studies involving 399 patients yielded a pooled sensitivity of 0.75 (95% confidence interval: 0.71-0.79) without heterogeneity or publication bias. The analysis of six studies involving 258 patients yielded a pooled specificity (other) of 0.95 (95% confidence interval: 0.92-0.98) without no heterogeneity or publication bias. We attempted to conduct a meta-analysis with the 10 studies involving 1916 patients to estimate specificity (unknown and other), but it remained unclear due to moderate heterogeneity and possible publication bias. In our meta-analysis, sensitivity of the index test was moderate and specificity (other) was high; however, the specificity (unknown and other) remained unclear.

Long-acting beta-agonists reduce mortality of patients with severe and very severe chronic obstructive pulmonary disease: a propensity score matching study.

BACKGROUND: Long-acting beta-agonists were one of the first-choice bronchodilator agents for stable chronic obstructive pulmonary disease. But the impact of long-acting beta-agonists on mortality was not well investigated. METHODS: National Emphysema Treatment Trial provided the data. Severe and very severe stable chronic obstructive pulmonary disease patients who were eligible for volume reduction surgery were recruited at 17 clinical centers in United States during 1988-2002. We used the 6-10 year follow-up data of patients randomized to non-surgery treatment. Hazard ratios for death by long-acting beta-agonists were estimated by three models using Cox proportional hazard analysis and propensity score matching were measured. RESULTS: The pre-matching cohort was comprised of 591 patients (50.6% were administered long-acting beta-agonists. Age: 66.6 ± 5.3 year old. Female: 35.4%. Forced expiratory volume in one second (%predicted): 26.7 ± 7.1%. Mortality during follow-up: 70.2%). Hazard ratio using a multivariate Cox model in the pre-matching cohort was 0.77 (P = 0.010). Propensity score matching was conducted (C-statics: 0.62. No parameter differed between cohorts). The propensity-matched cohort was comprised of 492 patients (50.0% were administered long-acting beta-agonists. Age: 66.8 ± 5.1 year old. Female: 34.8%. Forced expiratory volume in one second (%predicted) 26.5 ± 6.8%. Mortality during follow-up: 69.1%). Hazard ratio using a univariate Cox model in the propensity-matched cohort was 0.77 (P = 0.017). Hazard ratio using a multivariate Cox model in the propensity-matched cohort was 0.76 (P = 0.011). CONCLUSIONS: Long-acting beta-agonists reduce mortality of severe and very severe chronic obstructive pulmonary disease patients.