An antiaromatic-walled nanospace.

Over the past few decades, several molecular cages, hosts and nanoporous materials enclosing nanometre-sized cavities have been reported1-5, including coordination-driven nanocages6. Such nanocages have found widespread use in molecular recognition, separation, stabilization and the promotion of unusual chemical reactions, among other applications3-10. Most of the reported nanospaces within molecular hosts are confined by aromatic walls, the properties of which help to determine the host-guest behaviour. However, cages with nanospaces surrounded by antiaromatic walls have not yet been developed, owing to the instability of antiaromatic compounds; as such, the effect of antiaromatic walls on the properties of nanospaces remains unknown. Here we demonstrate the construction of an antiaromatic-walled nanospace within a self-assembled cage composed of four metal ions with six identical antiaromatic walls. Calculations indicate that the magnetic effects of the antiaromatic moieties surrounding this nanospace reinforce each other. This prediction is confirmed by 1H nuclear magnetic resonance (NMR) signals of bound guest molecules, which are observed at chemical shift values of up to 24 parts per million (ppm), owing to the combined antiaromatic deshielding effect of the surrounding rings. This value, shifted 15 ppm from that of the free guest, is the largest 1H NMR chemical shift displacement resulting from an antiaromatic environment observed so far. This cage may thus be considered as a type of NMR shift reagent, moving guest signals well beyond the usual NMR frequency range and opening the way to further probing the effects of an antiaromatic environment on a nanospace.

Efficacy of an oscillating positive expiratory pressure device in patients with Mycobacterium avium complex pulmonary disease.

Patients with Mycobacterium avium complex pulmonary disease (MAC-PD) often suffer from chronic symptoms such as sputum production, which reduces quality of life. Oscillatory positive expiratory pressure (OPEP) devices are used in physiotherapy to promote the clearance of respiratory secretions. We report two cases of improved lung function and improved scores on the Leicester Cough Questionnaire (LCQ) and the Breathlessness, Cough and Sputum Scale (BCSS) after the use of OPEP in patients with MAC-PD where treatment with guideline-based therapy, including amikacin liposome inhalation suspension, had proved ineffective for symptoms. Use of OPEP might maximize the efficacy of therapy and thereby improves outcomes in patients with MAC-PD. It is important to use both guideline-based therapy and OPEP, especially in patients whose health-related quality of life is affected by sputum symptoms. Further prospective studies are warranted to assess the benefit of adding OPEP to guidelines concerning therapy for patients with MAC-PD and sputum symptoms.

Changes in skin discoloration according to clofazimine dosage in nontuberculous mycobacterial pulmonary disease.

Although clofazimine is currently one of the standard regimens for Mycobacterium abscessus, it frequently causes skin discoloration, posing esthetic concerns for patients. We studied thirteen Asian patients with pulmonary nontuberculous mycobacterial disease treated with clofazimine at the NHO Kinki Chuo Chest Medical Center. In three patients (two women and one man) whose dosing regimens were altered owing to skin discoloration, we continuously measured luminance (L*), red-green (a*), and yellow-blue (b*) values (using a colorimeter) in both sun-exposed and sun-unexposed skin areas at each visit. Compared to baseline L* and a* values, the ΔL* values were negative (decreased brightness) and Δa* values were positive (increased redness) while patients received daily clofazimine. After switching to intermittent or reduced dosing, these changes gradually diminished. If such a dose reduction does not affect the therapeutic outcome, an even lower clofazimine dose may be attempted to minimize skin adverse effects.

A Role in 15-Deacetylcalonectrin Acetylation in the Non-Enzymatic Cyclization of an Earlier Bicyclic Intermediate in Fusarium Trichothecene Biosynthesis.

The trichothecene biosynthesis in Fusarium begins with the cyclization of farnesyl pyrophosphate to trichodiene, followed by subsequent oxygenation to isotrichotriol. This initial bicyclic intermediate is further cyclized to isotrichodermol (ITDmol), a tricyclic precursor with a toxic trichothecene skeleton. Although the first cyclization and subsequent oxygenation are catalyzed by enzymes encoded by Tri5 and Tri4, the second cyclization occurs non-enzymatically. Following ITDmol formation, the enzymes encoded by Tri101, Tri11, Tri3, and Tri1 catalyze 3-O-acetylation, 15-hydroxylation, 15-O-acetylation, and A-ring oxygenation, respectively. In this study, we extensively analyzed the metabolites of the corresponding pathway-blocked mutants of Fusarium graminearum. The disruption of these Tri genes, except Tri3, led to the accumulation of tricyclic trichothecenes as the main products: ITDmol due to Tri101 disruption; a mixture of isotrichodermin (ITD), 7-hydroxyisotrichodermin (7-HIT), and 8-hydroxyisotrichodermin (8-HIT) due to Tri11 disruption; and a mixture of calonectrin and 3-deacetylcalonectrin due to Tri1 disruption. However, the ΔFgtri3 mutant accumulated substantial amounts of bicyclic metabolites, isotrichotriol and trichotriol, in addition to tricyclic 15-deacetylcalonectrin (15-deCAL). The ΔFgtri5ΔFgtri3 double gene disruptant transformed ITD into 7-HIT, 8-HIT, and 15-deCAL. The deletion of FgTri3 and overexpression of Tri6 and Tri10 trichothecene regulatory genes did not result in the accumulation of 15-deCAL in the transgenic strain. Thus, the absence of Tri3p and/or the presence of a small amount of 15-deCAL adversely affected the non-enzymatic second cyclization and C-15 hydroxylation steps.

Metal Complex Molecular Junctions as Thermoelectric Devices.

Single-molecule junctions and self-assembled monolayer junctions are attractive architectures for thermoelectric devices. However, given the poor thermoelectric performance of organic molecules investigated so far, molecules characterized by high conductance and Seebeck coefficient values are desired to be explored. Metal complexes are promising possible active components of high-performance thermoelectric devices given that metal-ligand combinations and functions can be made to vary to modulate the transmission functions, thus strongly influencing conductance and Seebeck coefficient. In this concept article are described recent studies wherein thermoelectric measurements were conducted on metal complex junctions. Furthermore, the potential for the use of the junctions in thermoelectric devices is discussed.

Transformation of Highly Hydrophobic Triarylphosphines into Amphiphiles via Staudinger Reaction with Hydrophilic Trichlorophenyl Azide.

Owing to its hydrophobic properties and reactivity, triarylphosphines (PAr3 ) are promising precursors for the development of new amphiphiles. However, an efficient and reliable synthetic method for amphiphiles based on highly hydrophobic PAr3 is still required. Herein, a straightforward transformation of highly hydrophobic PAr3 into amphiphiles via the Staudinger reaction is reported. By simply mixing PAr3 and a hydrophilic trichlorophenyl azide containing two hydrophilic chains, amphiphiles bearing a N=P bond (i. e., an azaylide moiety) were quantitatively formed. The obtained azaylide-based amphiphiles were remarkably water-soluble, enabling their spontaneous self-assembly into 2 nm-sized micelles composed of 4-5 molecules in water with a low critical micelle concentration (up to 0.05 mM or less) due to the effective intermolecular interactions among the hydrophobic surfaces. Although the azaylide moiety is easily hydrolyzed in the presence of water, the azaylide in the amphiphiles displayed notable stability in water even at 60 h, which stems from the LUMO modulation induced by the presence of three electron-withdrawing chloro groups and two twisted alkoxycarbonyl groups, according to DFT calculations. An amphiphile having a large hydrophobic surface solubilized various hydrophobic organic dyes through efficient intermolecular interactions, resulting in the dyes exhibiting either monomer or excimer emissions in water.

Synthesis of multivalent fatty acid-conjugated antisense oligonucleotides: Cell internalization, physical properties, and in vitro and in vivo activities.

Herein, we describe the design and synthesis of multi-conjugatable fatty acid monomer phosphoramidites and their conjugation to antisense oligonucleotides (ASOs). Multivalent long-chain fatty acid conjugation improved the cellular uptake of ASOs but decreased in vitro activity due to alterations in physical properties and cellular localization. In addition, multivalently fatty acid-conjugated ASOs showed different organ specificity compared with that of unconjugated ASO in in vivo experiment. Although optimization of the linker structure between the fatty acid moiety and the ASO may be required, divalent long-chain fatty acid conjugation provides a new approach to increase endocytosis, thereby potentially improving the activity of therapeutic ASOs.

The Associated Factors of Low Birthweight Among Term Singletons in Japan: A Pregnancy Birth Registry Analysis.

BACKGROUND: Progress in reducing the global low birthweight (LBW) has been insufficient. Although the focus has been on preventing preterm birth, evidence regarding LBW in term births is limited. Despite its low preterm birth prevalence, Japan has a higher LBW proportion than other developed countries. This study aimed to examine the prevalence of LBW in term singleton births and its associated factors using a national database. METHODS: We retrospectively analyzed the data of neonates registered in the Japan Society of Obstetrics and Gynecology Successive Pregnancy Birth Registry System who were born 2013-2017. Exclusion criteria included stillbirths, delivery after 42 gestational weeks, and missing data. Logistic regression analyses were performed to investigate the maternal and perinatal factors associated with LBW in term singletons using the data of 715,414 singleton neonates. RESULTS: The overall prevalence of LBW was 18.3%, and 35.7% of LBWs originated from singleton term pregnancies. Multiple logistic regression analyses indicated that both modifiable and non-modifiable factors were independently associated with LBW in term neonates. The modifiable maternal factors included pre-pregnancy underweight, inadequate gestational weight gain, and smoking during pregnancy, while the non-modifiable factors included younger maternal age, nulliparity, hypertensive disorders of pregnancy, cesarean section delivery, female offspring, and congenital anomalies. CONCLUSION: Using the Japanese pregnancy birth registry data, more than one-third of LBWs were found to originate from singleton term pregnancies. Both modifiable and non-modifiable factors were independently associated with LBW in term neonates. Prevention strategies on modifiable risk factor control will be effective in reducing LBW worldwide.

Impact of postoperative intra-abdominal infectious complications on survival outcomes in patients with gastric cancer who underwent laparoscopic surgery.

BACKGROUND: Postoperative intra-abdominal infection is known to adversely affect survival outcomes in patients with gastric cancer; however, previous reports have investigated this complication only in open surgery. This adverse effect is expected to be weakened by less invasive surgery, such as a laparoscopic approach, by way of maintaining immune function. METHODS: This study included 1223 patients with gastric cancer who underwent open (n = 439) or laparoscopic (n = 784) curative surgery between 2010 and 2015. For each approach, patients were divided into two groups based on presence or absence of postoperative intra-abdominal infection of Clavien-Dindo grade II or higher (C-group and NC-group, respectively). Survival outcomes were compared in propensity-matched cohorts to evaluate the impact of the complication. RESULTS: The incidences of Clavien-Dindo ≥ grade II postoperative intra-abdominal infectious complications were 9.7% (43/439) in open surgery and 9.8% (70/714) in laparoscopic surgery. After propensity score matching, 86 patients in open surgery and 138 in laparoscopic surgery were extracted for analysis. The 5-year overall survival rate in the open C-group (n = 43) was worse than that in the open NC-group (n = 43) but with no significant difference (70.9% vs. 82.8%, log-rank P = 0.18). The 5-year overall survival rates were equivalent between the laparoscopic C-group (n = 69) and the laparoscopic NC-group (n = 69) (90.5% vs. 90.4%, log-rank P = 0.99). CONCLUSION: In general, postoperative intra-abdominal infection adversely affects survival outcomes; however, its impact may be weakened by less invasive surgery. Further evaluation using larger datasets is necessary before reaching definitive conclusions.

Obstetric outcomes after medroxyprogesterone acetate treatment for early stage endometrial cancer or atypical endometrial hyperplasia: a single hospital-based study.

BACKGROUND: To investigate perinatal outcomes in pregnancy after high-dose medroxyprogesterone acetate (MPA) therapy for early stage endometrial cancer (EC) and atypical endometrial hyperplasia (AEH) and to determine whether pregnancy after MPA therapy is at a higher risk of placenta accreta. METHODS: Data of 51 pregnancies in 46 women who received MPA therapy for EC or AEH and delivered after 22 weeks of gestation at Keio University Hospital were reviewed. A retrospective matched case-control study was performed to determine the risk of placenta accreta in pregnancy after MPA therapy compared with singleton pregnancies without any history of maternal malignancy treatments. RESULTS: The incidence of placenta accreta was higher in the MPA group than in the control group (15.7 vs. 0%, p = 0.0058). However, no differences in other perinatal outcomes were observed between groups. While gestational weeks at delivery in the MPA group were later than those in the control group (p = 0.0058), no difference in the incidence of preterm delivery was recorded between groups. In the MPA therapy group, the number of patients who underwent ≥ 6 dilation and curettage (D&C) was higher in the placenta accreta group than in the non-placenta accreta group (50.0 vs. 14.0%, p = 0.018). Patients with ≥ 6 D&Cs demonstrated a 6.0-fold increased risk of placenta accreta (p = 0.043, 95% CI 1.05-34.1) than those receiving ≤ 3 D&Cs. CONCLUSION: Pregnancy after MPA therapy is associated with a high risk of placenta accreta. In cases in which the frequency of D&C is high, placenta accreta should be considered.

High Seebeck Coefficient Achieved by Multinuclear Organometallic Molecular Junctions.

This paper describes the thermoelectric properties of molecular junctions incorporating multinuclear ruthenium alkynyl complexes that comprise Ru(dppe)2 [dppe = 1,2-bis(diphenylphosphino)ethane] fragments and diethylnyl aromatic bridging ligands with thioether anchors. Using the liquid metal technique, the Seebeck coefficient was examined as a function of metal nuclearity, oxidation state, and substituent on the organic ligand backbone. High Seebeck coefficients up to 73 µV/K and appreciable thermal stability with thermovoltage up to ∼3.3 mV at a heating temperature of 423 K were observed. An unusually high proximity of the highest occupied molecular orbital (HOMO) energy level to the Fermi level was revealed to give the remarkable thermoelectric performance as suggested by combined experiments and calculations. This work offers important insights into the development of molecular-scale devices for efficient thermoregulation and heat-to-electricity conversion.

[A CASE OF SUSPECTED ALLERGIC BRONCHOPULMONARY MYCOSIS CAUSED BY SCEDOSPORIUM APIOSPERMUM THAT SHOWED CLINICAL IMPROVEMENT AFTER BRONCHOSCOPIC REMOVAL OF A MUCUS PLUG].

A 69-year-old woman presented with a persistent cough and high fever. Thoracic computed tomography revealed atelectasis and high-attenuation mucus. The blood test results showed eosinophils at 18.2%, an absolute eosinophil count of 980 cells/µL, and a total serum immunoglobulin E of 1980IU/mL. Bronchoscopy revealed a mucous plug, which upon photomicrograph examination, showed eosinophils. A culture study of the mucus yielded Scedosporium apiospermum, leading to the suspicion of allergic bronchopulmonary mycosis (ABPM) caused by the fungus. After the bronchoscopic removal of the mucous plug, her symptoms quickly diminished. She was successfully treated without medication, and ABPM has not recurred for 2 years. To our knowledge, ABPM caused by Scedosporium apiospermum is rare, and close follow-up was effective without the administration of systemic steroids or antifungal drugs.

A Redox-Responsive Ferrocene-Based Capsule Displaying Unusual Encapsulation-Induced Charge-Transfer Interactions.

A ferrocene-based capsule is spontaneously and quantitatively formed in water by the assembly of bent amphiphiles carrying two ferrocene units. The disassembly and assembly of the new organometallic capsule, with a well-defined and highly condensed ferrocene core, are demonstrated by chemical redox stimuli in a fully reversible fashion under ambient conditions. In contrast to previously reported multiferrocene assemblies, only the present capsule efficiently encapsulates typical organic/inorganic dyes as well as electron-accepting molecules in water. As a result, unusual host-guest charge-transfer (CT) interactions, displaying relatively wide absorption bands in the visible to near-infrared region (λ=650-1350 nm), are observed upon the encapsulation of acceptors (i.e., chloranil and TCNQ). The resultant encapsulation-induced CT interactions can be released by a redox stimulus through the disassembly of the capsule.

Regulation of Ribonuclease J Expression in Corynebacterium glutamicum.

RNase J exerts both 5'-3' exoribonuclease and endoribonuclease activities and plays a major role in ribonucleotide metabolism in various bacteria; however, its gene regulation is not well understood. In this study, we investigated the regulation of rnj expression in Corynebacterium glutamicum. rnj mRNA expression was increased in a strain with an rnj mutation. Deletion of the genes encoding RNase E/G also resulted in increased rnj mRNA levels, although the effect was smaller than that of the rnj mutation. rnj mRNA was more stable in the rnj mutant strain than in wild-type cells. These results indicate that RNase J regulates its own gene by degrading its mRNA. The growth of rnj and pnp mutant cells was impaired at cold temperatures. The expression of rnj mRNA was transiently induced by cold shock; however, this induction was not observed in the rnj mutant strain, suggesting that autoregulation by self-degradation is responsible for inducing of rnj expression under cold-shock conditions. IMPORTANCE Corynebacterium glutamicum harbors one RNase E/G-type enzyme and one RNase J-type enzyme which are major ribonucleases in various bacteria. However, little is known about these gene regulations. Here, we show that RNase J autoregulates its own gene expression and RNase E/G is also involved in the rnj mRNA degradation. Furthermore, we show that transient induction of the rnj mRNA in the cold-shock condition is dependent on RNase J autoregulation. This study sheds light on the regulatory mechanism of RNase J in C. glutamicum.

Acene Size-Dependent Transition of The Radical Centers From the Metal to The Acene Parts In Monocationic Dinuclear (Diethynylacene)diyl Complexes.

Controlling radical localization/delocalization is important for functional materials. The present paper describes synthesis and results of electrochemical, spectroscopic, and theoretical studies of diruthenium (p-diethynylacene)diyl complexes, Me3 Si-(C≡C)2 -Ru(dppe)2 -C≡C-Ar-C≡C-Ru(dppe)2 -(C≡C)2 -SiMe3 (1-6) (dppe: 1,2-bis(diphenylphosphino)ethane), and their monocationic radical species ([1]+ -[6]+ ). The HOMO-LUMO energy gaps can be finely tuned by the acene rings in the bridging ligands installed, as indicated by the absorption maxima of the electronic spectra of 1-6 ranging from the UV region even to the NIR region. The cationic species [1]+ -[6]+ show two characteristic NIR bands, which are ascribed to the charge resonance (CR) and π-π* transition bands, as revealed by spectroelectrochemistry. Expansion of the acene rings in [1]+ -[6]+ causes (1) blue shifts of the CR bands and red shifts of the π-π* transition bands and (2) charge localization on the acene parts as evidenced by the ESR, DFT and TD-DFT analyses. Notably, the monocationic complexes of the larger acene derivatives are characterized as the non-classical acene-localized radicals.

Selective Encapsulation and Unusual Stabilization of cis-Isomers by a Spherical Polyaromatic Cavity.

To explore new cavity functions, we herein employed cis-trans stereoisomers with a N=N, C=C, or C=N unit as guest indicators for a polyaromatic capsule. Thanks to the rigid, spherical cavity with a diameter of ∼1 nm, azobenzene and stilbene derivatives are quantitatively encapsulated by the capsule with 100 % cis-selectivity in water. The isomerization of the cis-azo compound is suppressed against heat and light in the cavity, due to the confinement effect. Furthermore, C,N-diphenyl imine derivatives are quantitatively encapsulated by the capsule in water and adopt an otherwise unstable cis-form. The polyaromatic cavity suppresses the hydrolysis of the imines in water, even at elevated temperature, due to the shielding effect. Accordingly, the properties of the cis-trans isomers could be largely altered through supramolecular manipulation.

CH-π Multi-Interaction-Driven Recognition and Isolation of Planar Compounds in a Spheroidal Polyaromatic Cavity.

π-π Interactions are established as a powerful supramolecular tool, whereas the usability of CH-π interactions has been rather limited so far. Here we present (i) selective binding of planar polyaromatics and (ii) effective isolation of planar metal complexes by a polyaromatic capsule, utilizing multiple CH-π interactions. In the spheroidal cavity, one molecule of large and medium-sized polyaromatic molecules (i. e., coronene and pyrene) is exclusively bound from mixtures bearing the same number of aromatic CH groups. Theoretical studies reveal that multiple host-guest CH-π interactions (up to 32 interactions) are the predominant driving force for the observed selectivity. In addition, one molecule of planar metal complexes (i. e., porphine and bis(acetylacetonato) Cu(II) complexes) is quantitatively bound by the capsule through aromatic and aliphatic CH-π multi-interactions, respectively. The ESR and theoretical studies demonstrate the isolation capability of the capsular framework and an unusual polar environment in the polyaromatic cavity.

Reduction in postoperative complications by robotic surgery: a case-control study of robotic versus conventional laparoscopic surgery for gastric cancer.

BACKGROUND: Robotic gastrectomy (RG) is being increasingly performed globally; it is considered an evolved type of conventional laparoscopic surgery with excellent dexterity and precision, but higher costs and longer operation time. Thus, there is a need to identify the benefits from RG and its specific candidates. METHODS: This retrospective study analyzed data from a prospectively collected clinical database at our center. Data of patients with primary gastric cancer undergoing either robotic or laparoscopic radical gastrectomy from June 2014 to June 2020 were reviewed. Surgical outcomes were compared between the two groups, and multivariable analyses were performed to elucidate the relevant factors for postoperative complications in several subgroups. RESULTS: A total of 1172 patients were divided into those who underwent RG (n = 152) and those who underwent laparoscopic gastrectomy (LG) (n = 1020). Baseline characteristics were similar in the two groups, except the RG group included more patients undergoing total/proximal gastrectomy (TG/PG) and patients at clinical stage III. Compared with the LG group, the RG group had lower incidences of postoperative complications ≥ Clavien-Dindo grade III (2/152 (1.3%) versus 72/1020 (7.1%); P = 0.004), and intraabdominal complications ≥ grade II (6/152 (3.9%) versus 119/1020 (11.7%); P = 0.004). Multivariable analysis revealed that RG was a significant relevant factor for reducing overall postoperative complications (≥ grade III) (odds ratio (OR) 0.16, P = 0.013), and intraabdominal complications (≥ grade II) (OR 0.29, P = 0.002). Subgroup analyses demonstrated that this tendency was enhanced in patients undergoing TG/PG (OR 0.29, P = 0.021) or at clinical stage II/III (OR 0.10, P = 0.027). CONCLUSIONS: RG reduces the incidence of postoperative complications compared with conventional LG and this tendency may be enhanced in technically complicated procedures with demanding anastomosis or D2 lymphadenectomy. Patients requiring such procedures would most benefit from RG.

Is oral food challenge test useful for avoiding complete elimination of cow's milk in Japanese patients with or suspected of having IgE-dependent cow's milk allergy?

BACKGROUND: Cow's milk, along with hen's egg, are common causes of food allergies in children worldwide. Accidental ingestion of milk is common and often induces severe allergic reactions. Oral food challenge test (OFC) is usually performed in patients with or suspected of having a food allergy. However, the evidence of whether cow's milk OFC is useful in IgE-dependent cow's milk allergy patients to avoid total elimination is not known. METHODS: After setting the clinical question and outcomes, we performed a systematic review for relevant articles published from January 1, 2000 to August 31, 2019 using PubMed® and Ichushi-Web databases. Each article was then evaluated for the level of evidence. All positive results of the OFC were defined as adverse events. RESULTS: Forty articles were selected in this study. Our review revealed that cow's milk OFC was able to avoid the complete elimination of cow's milk in 66% of the patients with cow's milk allergy. We also found that adverse events occurred frequently (50.5%). CONCLUSIONS: This analysis supports the recommendation of conducting cow's milk OFC to avoid complete elimination of cow's milk, however the test should be conducted with careful consideration of the patient's safety. As the methods of OFC and subjects varied among the articles selected in this study, further studies are needed to obtain higher quality evidence.

[SEVERE INFANTILE ASTHMA TREATED WITH LONG-ACTING MUSCARINIC ANTAGONIST: A CASE SERIES].

BACKGROUND: Long-acting muscarinic antagonists (LAMA) are used for long-term treatment of bronchial asthma in adults. Its use in the management of pediatric bronchial asthma, however, is currently not approved in Japan. Nonetheless, there have been a few reports of its use in children, particularly in cases of severe bronchial asthma or those without atopic disease that are refractory to existing treatment protocols. We report the progress of LAMA in infantile asthma patients. CASES: Three out of four patients had LAMA introduced at 3 to 5 years of age after being diagnosed with asthma at 1 to 3 years old. Three patients had non-IgE-related asthma and an underlying disease, such as Apert and Noonan syndrome, while one patient had severe IgE-related asthma without a pre-existing disease. In all cases, conventional long-term medications such as medium to high-dose inhaled corticosteroids and long-acting beta-agonists, were given. However, severe bronchial asthma persisted, with some patients having uncontrolled secretions. Since uncontrolled severe-persistent bronchial asthma results in repeated hospitalization and intensive care unit admission, we introduced LAMA, specifically 2.5µg/day of tiotropium (Tio). After the introducing Tio, none of the patients had an acute exacerbation that required hospitalization and the frequency of wheezing was reduced. LAMA was administered for up to 19 months, with no adverse events. CONCLUSION: The results of this series suggest that LAMA is an effective and safe option for uncontrolled infantile asthma.