Structural and Functional Analysis of the Amorphous Calcium Carbonate-Binding Protein Paramyosin in the Shell of the Pearl Oyster, Pinctada fucata.

Amorphous calcium carbonate (ACC) is an important precursor phase for the formation of aragonite crystals in the shells of Pinctada fucata. To identify the ACC-binding protein in the inner aragonite layer of the shell, extracts from the shell were used in the ACC-binding experiments. Semiquantitative analyses using liquid chromatography-mass spectrometry revealed that paramyosin was strongly associated with ACC in the shell. We discovered that paramyosin, a major component of the adductor muscle, was included in the myostracum, which is the microstructure of the shell attached to the adductor muscle. Purified paramyosin accumulates calcium carbonate and induces the prism structure of aragonite crystals, which is related to the morphology of prism aragonite crystals in the myostracum. Nuclear magnetic resonance measurements revealed that the Glu-rich region was bound to ACC. Activity of the Glu-rich region was stronger than that of the Asp-rich region. These results suggest that paramyosin in the adductor muscle is involved in the formation of aragonite prisms in the myostracum.

Plasma D-Dimer Levels Can Provide Useful Diagnostic Information on Acute Vertebral Compression Fractures in Patients with Low Back Pain in the Emergency Room.

BACKGROUND: Patients with acute vertebral compression fractures (aVCFs) are frequently transferred to an emergency department by ambulance. The most useful imaging modality is magnetic resonance imaging (MRI); however, which patients should be prioritized for MRI evaluation may be unclear. The aim of this study was to evaluate plasma D-dimer levels as a biomarker for aVCFs. METHODS: This retrospective cohort study included patients with low back pain in the emergency department between November 2017 and October 2020. Patients with infections, patients with coagulation disorders, and patients without D-dimer level measurements were excluded. The presence of an aVCF was detected with MRI. Blood samples were collected for routine blood tests. The predictive factors for aVCFs were evaluated with univariate and multivariable logistic regression analyses. RESULTS: Overall, 191 consecutive MRI evaluations were ordered. After exclusions, 101 patients were reviewed. Based on MRI, 65 (64.4%) patients were diagnosed with aVCF. The presence of aVCF was significantly correlated with age (odds ratio [OR] = 1.052, 95% confidence interval [CI] 1.018-1.191), an old vertebral compression fracture (OR = 3.290, 95% CI 1.342-8.075), hemoglobin (OR = 0.699, 95% CI 0.535-0.912), and D-dimer levels (OR = 1.829, 95% CI 1.260-2.656). Results from a multivariable logistic regression analysis showed that D-dimer levels (OR = 1.642, 95% CI 1.188-2.228) remained a significant risk factor for the presence of aVCFs after adjustment for potential confounders. CONCLUSIONS: Plasma D-dimer levels can provide useful diagnostic information about whether an aVCF is present.

Efficacy of dupilumab for airway hypersecretion and airway wall thickening in patients with moderate-to-severe asthma: A prospective, observational study.

BACKGROUND: Dupilumab has clinical effects in patients with moderate-to-severe asthma. When considering interleukin (IL)-4 and IL-13 signaling, effects of dupilumab on airway mucus hypersecretion and airway remodeling are expected, but they have been reported in only a few short-term studies. Its efficacy for airway hyperresponsiveness (AHR) remains unknown. We comprehensively assessed the efficacy of dupilumab, especially for subjective and objective measures of airway mucus hypersecretion and airway dimensions in moderate-to-severe asthmatic patients. METHODS: In 28 adult patients with moderate-to-severe uncontrolled asthma, the comprehensive efficacy of 48-week dupilumab treatment, including the Cough and Sputum Assessment Questionnaire (CASA-Q), radiological mucus scores and airway dimensions on computed tomography (CT), was assessed prospectively. Treatment responsiveness to dupilumab was analyzed. RESULTS: With 48-week dupilumab treatment, all four cough and sputum domain scores of CASA-Q improved significantly. Radiological mucus scores and airway wall thickening on CT were significantly decreased. The decreases in mucus scores were significantly associated with improvements in Asthma Control Questionnaire scores, Asthma Quality of Life Questionnaire (AQLQ) overall scores, airway obstruction, and airway type 2 inflammation. When defined by > 0.5 improvement in AQLQ overall scores, 18 patients (64%) were identified as responders. CONCLUSIONS: Dupilumab reversed subjective and objective measures of airway mucus hypersecretion and some aspects of airway remodeling in patients with moderate-to-severe uncontrolled asthma.

Microvascular Decompression for Trigeminal Neuralgia with Complicated Offending Vessel Involving Trigeminocerebellar Artery: 2-Dimensional Operative Video.

Microvascular decompression (MVD) is a well-established and definitive treatment option for trigeminal neuralgia (TN).1 However, complex vascular geometry and numerous offending vessels make it difficult to perform nerve decompression in certain cases.2 The trigeminocerebellar artery (TCA) is a unique branch of the basilar artery. The vessel is named the TCA because it supplies both the trigeminal nerve root and the cerebellar hemisphere.3 This anatomical variant may increase the risk of neurovascular compression in the trigeminal nerve. We present the case of a 74-year-old man with left TN in whom a TCA was one of the responsible compression vessels. Preoperative images revealed the ipsilateral anterior inferior cerebellar artery, well-developed TCA, and superior cerebellar artery, wherein these branches were all suspected to be involved in trigeminal nerve compression. In MVD, 3 arteries were suspected to compress the trigeminal nerve in 5 sites, and all of them needed to be meticulously dissected from the nerve root and decompressed. Moreover, 2 of them branched many short perforators to the brainstem. Three decompression procedures (transposition to the dura, transposition to the brain, and interposition) were performed to decompress the trigeminal nerve. Postoperatively, TN was completely resolved immediately. MVD for TN could be difficult to perform in cases with TCA, as in the present case, and rigorous procedures were required intraoperatively.

A Case of Symptomatic Multiple Tarlov Cysts Treated with Microsurgical Wrapping Technique -Efficacy and Limitation of Surgical Procedure.

Tarlov cysts (TCs) rarely cause clinical symptoms, such as leg pain, buttock pain, and bladder/bowel dysfunction. Surgery is considered when these symptoms persist despite medical treatments. Among several surgical procedures, microsurgical wrapping (MSW) is a relatively novel, simple technique with few complications, including cerebrospinal fluid leakage. Herein, we report a case of multiple TCs treated with MSW and present the mechanism of symptoms generated by TC and the procedure's limitations. A 58-year-old man complained of severe right leg and buttock pain for 3 months and was admitted to our hospital. His symptoms aggravated with sitting and standing and improved with the prone position. Spinal magnetic resonance imaging (MRI) demonstrated multiple sacral cysts containing intense cerebrospinal fluid. The cysts connect to the right S3 and S4 nerve roots. He was treated conservatively with medications; however, his symptoms were not improved. Therefore, MSW was performed for TCs connected to the S3 and S4 roots. The postoperative course was uneventful, and cerebrospinal fluid leakage did not occur. MRI performed 1 year after the operation demonstrated no recurrence of the TCs, and his leg pain was completely relieved; however, the buttock pain remained. MSW for TCs is effective for symptoms of adjacent nerve root compression; however, repairing the damaged nerve root in TCs is sometimes difficult. This may be a limitation of present surgical interventions because these symptoms may be difficult to treat even with other interventions.

Skin care by washing with water is not inferior to washing with a cleanser in children with atopic dermatitis in remission in summer: WASH study.

BACKGROUND: Washing with water is not inferior to washing with soaps and detergents in children with atopic dermatitis (AD) in remission during the fall-winter seasons. We investigated whether this finding varies during summer based on the type of cleanser (soaps and detergents). METHODS: This evaluator-blinded, pragmatic, randomized, and non-inferiority study enrolled patients with AD whose eczema was controlled following regular steroid ointment application 2 days/week. For 8 ± 4 weeks, participants washed their upper and lower limbs with a cleanser on one side and with water alone on the other. Each participant chose either a weakly alkaline soap or an acidic detergent. The primary outcome was the Eczema Area and Severity Index (EASI) score at week 8 ± 4. RESULTS: The data of 43 of the 47 registered participants were analyzed. The median patient age was 44 (23-99) months; 28 and 15 participants chose weakly alkaline and acidic cleansers, respectively. At week 8 ± 4, EASI scores of the water and cleanser sides were 0.00 (0.00-0.40) and 0.15 (0.00-0.40), respectively (p = 0.74). The difference between both sides was 0.00 (-0.07 to 0.14); the limits of the 95 % confidence interval did not reach the pre-specified non-inferiority margin. No difference was observed in the median Patient-Oriented Eczema Measure score, number of additional steroid ointment applications, and occurrences of skin infections. There were no differences between the cleanser types in any of the results. CONCLUSIONS: We demonstrated that washing with water was not inferior to that with a cleanser in patients with AD in the maintenance phase during summer, regardless of the type of cleanser.

Factors influencing slippage after microsurgical single level lumbar spinal decompression surgery - Are the psoas and multifidus muscles involved?

PURPOSE: Patients with lumbar spinal stenosis (LSS) require microsurgical decompression (MSD) surgery; however, MSD is often associated with postoperative instability at the operated level. Paraspinal muscles support the spinal column; lately, paraspinal volume has been used as a good indicator of sarcopenia. This study aimed to determine preoperative radiological factors, including paraspinal muscle volume, associated with postoperative slippage progression after MSD in LSS patients. METHODS: Patients undergoing single-level (L3/4 or L4/5) MSD for symptomatic LSS and followed-up for ≥ 5 years in our institute were reviewed retrospectively to measure preoperative imaging parameters focused on the operated level. Paraspinal muscle volumes (psoas muscle index [PMI] and multifidus muscle index [MFMI]) defined using the total cross-sectional area of each muscle/L3 vertebral body area in the preoperative lumbar axial CT) were calculated. Postoperative slippage in the form of static translation (ST) ≥ 2 mm was assessed on the last follow-up X-ray. RESULTS: We included 95 patients with average age and follow-up periods of 69 ± 8.2 years and 7.51 ± 2.58 years, respectively. PMI and MFMI were significantly correlated with age and significantly larger in male patients. Female sex, preoperative ST, dynamic translation, sagittal rotation angle, facet angle, pelvic incidence, lumbar lordosis, and PMI were correlated with long-term postoperative worsening of ST. However, as per multivariate analysis, no independent factor was associated with postoperative slippage progression. CONCLUSION: Lower preoperative psoas muscle volume in LSS patients is an important predictive factor of postoperative slippage progression at the operated level after MSD. The predictors for postoperative slippage progression are multifactorial; however, a well-structured postoperative exercise regimen involving psoas muscle strengthening may be beneficial in LSS patients after MSD.

Structural insights into the complex of oncogenic KRas4BG12V and Rgl2, a RalA/B activator.

About a quarter of total human cancers carry mutations in Ras isoforms. Accumulating evidence suggests that small GTPases, RalA, and RalB, and their activators, Ral guanine nucleotide exchange factors (RalGEFs), play an essential role in oncogenic Ras-induced signalling. We studied the interaction between human KRas4B and the Ras association (RA) domain of Rgl2 (Rgl2RA), one of the RA-containing RalGEFs. We show that the G12V oncogenic KRas4B mutation changes the interaction kinetics with Rgl2RA The crystal structure of the KRas4BG12V: Rgl2RA complex shows a 2:2 heterotetramer where the switch I and switch II regions of each KRasG12V interact with both Rgl2RA molecules. This structural arrangement is highly similar to the HRasE31K:RALGDSRA crystal structure and is distinct from the well-characterised Ras:Raf complex. Interestingly, the G12V mutation was found at the dimer interface of KRas4BG12V with its partner. Our study reveals a potentially distinct mode of Ras:effector complex formation by RalGEFs and offers a possible mechanistic explanation for how the oncogenic KRas4BG12V hyperactivates the RalA/B pathway.

Changes in spinal sagittal balance after a new osteoporotic vertebral compression fracture.

We conduct a longitudinal study to examine how new VCF alter spinal sagittal balance. New VCF increased SVA by an average of 2.8 cm. Sagittal balance deteriorates as a VCF develops in the lower lumbar spine. A new fracture below L1 increased the relative risk of a deterioration of sagittal balance 2.9-fold compared to one above Th12. PURPOSE: Studies on the relationship between osteoporotic vertebral fractures and spinal sagittal balance have all been limited to cross-sectional studies. The aim of this study is to conduct a longitudinal study to examine how new vertebral compression fracture (VCF) alter spinal sagittal balance. METHODS: Subjects were patients undergoing periodic examinations after treatment of a vertebral fracture or lumbar spinal canal stenosis. Forty patients who developed a new VCF were included in this study. Full-spine standing radiographs were compared before and after the fracture to examine changes in spinopelvic parameters and factors determining the changes in sagittal balance. RESULTS: The mean age of the patients was 79.0 years. The mean interval between pre- and post-fracture radiographs was 22.7 months, and the mean time between development of a fracture and post-fracture radiographs was 4.6 months. After a fracture, sagittal vertical axis (SVA) increased an average of 2.78 cm and spino-sacral angle (SSA) decreased an average of 5.3°. Both ⊿SVA and ⊿SSA were not related to pre-fracture parameters. The wedge angle of the fractured vertebra was not related to changes in sagittal balance. ⊿SVA increased markedly in patients with a fracture of the lower lumbar vertebrae. receiver operating characteristic analysis revealed that the relative risk of a deterioration of sagittal balance was 2.9 times higher for a new fracture below L1 than for a fracture above Th12. CONCLUSION: New VCF increased SVA by an average of 2.8 cm. Sagittal balance deteriorates as a new fracture develops in the lower lumbar spine. Early intervention in osteoporosis is vital for the elderly.

Low Daily Step Count Associated with Small Erector Spine Muscle Area and Sarcopenia in Idiopathic Pulmonary Fibrosis.

Objective The daily step count is associated with mortality in idiopathic pulmonary fibrosis (IPF). However, the factors associated with this phenomenon are not yet fully understood. We therefore clarified its association with clinical parameters. Methods Fifty-nine patients with IPF with available data for daily step counts; 6-minute walk distance (6MWD); chest, abdominal, and pelvic computed tomography (CT); pulmonary function; psychological evaluations; and sarcopenia assessments were prospectively enrolled. The daily step count was measured continuously for seven consecutive days. The cross-sectional areas of the erector spinae muscles at the level of the 12th vertebra (ESMCSA) and psoas major muscle volume (PMV) obtained by CT were assessed. Results The average age of the patients was 73.3±8.1 years old, and the percent predicted forced vital capacity was 81.6% ±15.8%. The average daily step count was 4,258 (2,155-6,991) steps. The average 6MWD, ESMCSA, and PMV were 413±97 m, 25.5±6.7 cm2, and 270±75.6 cm3, respectively. A linear regression analysis for daily step count showed that the ESMCSA and 6MWD were independent factors for the daily step count, whereas the PMV and skeletal muscle index were not. The daily step count, ESMCSA, and 6MWD were lower in patients with sarcopenia than in those without sarcopenia. Conclusions A lower daily step count was associated with a smaller erector spinae muscle area and sarcopenia in patients with IPF. Further studies are warranted to confirm the importance of physical therapy for muscle strengthening in patients with IPF.

Ablation of Dual-Specificity Phosphatase 6 Protects against Nonalcoholic Fatty Liver Disease via Cytochrome P450 4A and Mitogen-Activated Protein Kinase.

Dual-specificity phosphatase 6 (DUSP6) is a specific phosphatase for mitogen-activated protein kinase (MAPK). This study used a high-fat diet (HFD)-induced murine nonalcoholic fatty liver disease model to investigate the role of DUSP6 in this disease. Wild-type (WT) and Dusp6-haploinsufficiency mice developed severe obesity and liver pathology consistent with nonalcoholic fatty liver disease when exposed to HFD. In contrast, Dusp6-knockout (KO) mice completely eliminated these phenotypes. Furthermore, primary hepatocytes isolated from WT mice exposed to palmitic and oleic acids exhibited abundant intracellular lipid accumulation, whereas hepatocytes from Dusp6-KO mice showed minimal lipid accumulation. Transcriptome analysis revealed significant down-regulation of genes encoding cytochrome P450 4A (CYP4A), known to promote ω-hydroxylation of fatty acids and hepatic steatosis, in Dusp6-KO hepatocytes compared with that in WT hepatocytes. Diminished CYP4A expression was observed in the liver of Dusp6-KO mice compared with WT and Dusp6-haploinsufficiency mice. Knockdown of DUSP6 in HepG2, a human liver-lineage cell line, also promoted a reduction of lipid accumulation, down-regulation of CYP4A, and up-regulation of phosphorylated/activated MAPK. Furthermore, inhibition of MAPK activity promoted lipid accumulation in DUSP6-knockdown HepG2 cells without affecting CYP4A expression, indicating that CYP4A expression is independent of MAPK activation. These findings highlight the significant role of DUSP6 in HFD-induced steatohepatitis through two distinct pathways involving CYP4A and MAPK.

Interactions of the N- and C-Terminal SH3 Domains of Drosophila Drk with the Proline-Rich Peptides from Sos and Dos.

Drk, a homologue of human GRB2 in Drosophila, receives signals from outside the cells through the interaction of its SH2 domain with the phospho-tyrosine residues in the intracellular regions of receptor tyrosine kinases (RTKs) such as Sevenless, and transduces the signals downstream through the association of its N- and C-terminal SH3 domains (Drk-NSH3 and Drk-CSH3, respectively) with proline-rich motifs (PRMs) in Son of Sevenless (Sos) or Daughter of Sevenless (Dos). Isolated Drk-NSH3 exhibits a conformational equilibrium between the folded and unfolded states, while Drk-CSH3 adopts only a folded confirmation. Drk interacts with PRMs of the PxxPxR motif in Sos and the PxxxRxxKP motif in Dos. Our previous study has shown that Drk-CSH3 can bind to Sos, but the interaction between Drk-NSH3 and Dos has not been investigated. To assess the affinities of both SH3 domains towards Sos and Dos, we conducted NMR titration experiments using peptides derived from Sos and Dos. Sos-S1 binds to Drk-NSH3 with the highest affinity, strongly suggesting that the Drk-Sos multivalent interaction is initiated by the binding of Sos-S1 and NSH3. Our results also revealed that the two Sos-derived PRMs clearly favour NSH3 for binding, whereas the two Dos-derived PRMs show almost similar affinity for NSH3 and CSH3. We have also performed docking simulations based on the chemical shift perturbations caused by the addition of Sos- and Dos-derived peptides. Finally, we discussed the various modes in the interactions of Drk with Sos/Dos.

Direct Observation of Membrane-Associated H-Ras in the Native Cellular Environment by In-Cell 19F-NMR Spectroscopy.

Ras acts as a molecular switch to control intracellular signaling on the plasma membrane (PM). Elucidating how Ras associates with PM in the native cellular environment is crucial for understanding its control mechanism. Here, we used in-cell nuclear magnetic resonance (NMR) spectroscopy combined with site-specific 19F-labeling to explore the membrane-associated states of H-Ras in living cells. The site-specific incorporation of p-trifluoromethoxyphenylalanine (OCF3Phe) at three different sites of H-Ras, i.e., Tyr32 in switch I, Tyr96 interacting with switch II, and Tyr157 on helix α5, allowed the characterization of their conformational states depending on the nucleotide-bound states and an oncogenic mutational state. Exogenously delivered 19F-labeled H-Ras protein containing a C-terminal hypervariable region was assimilated via endogenous membrane-trafficking, enabling proper association with the cell membrane compartments. Despite poor sensitivity of the in-cell NMR spectra of membrane-associated H-Ras, the Bayesian spectral deconvolution identified distinct signal components on three 19F-labeled sites, thus offering the conformational multiplicity of H-Ras on the PM. Our study may be helpful in elucidating the atomic-scale picture of membrane-associated proteins in living cells.

Bronchial thermoplasty improves cough hypersensitivity and cough in severe asthmatics.

BACKGROUND: Cough is a troublesome symptom of asthma because it is associated with disease severity and poor asthma control. Bronchial thermoplasty (BT) may be effective in improving cough severity and cough-related quality of life in severe uncontrolled asthma. OBJECTIVE: To evaluate the efficacy of BT for cough in severe uncontrolled asthma. METHODS: Twelve patients with severe uncontrolled asthma were enrolled in this study between 2018 May and March 2021 and arbitrarily divided into cough-predominant [cough severity Visual Analog Scale (VAS) ≥ 40 mm, n = 8] and typical asthma (cough VAS <40 mm, n = 4) groups. Clinical parameters, such as capsaicin cough sensitivity [C-CS: the concentrations to inhaled capsaicin required to induce at least two (C2) and five (C5) coughs], lung function, and type-2-related biomarkers (fractional nitric oxides and absolute eosinophil counts) and cough-related indices [cough severity VAS and the Leicester Cough Questionnaire (LCQ)] were evaluated before and 3 months after performing BT. RESULTS: BT significantly improved both cough-related indices and C-CS in the cough-predominant group. Changes in C-CS were significantly correlated with changes in the LCQ scores (C5: r = 0.65, p = 0.02 for all patients, and r = 0.81, p = 0.01 for the cough-predominant group). CONCLUSIONS: BT may be effective for cough in severe uncontrolled asthma by improving C-CS. However, further larger cohort studies are necessary to confirm the effect of BT for cough in asthma. CLINICAL TRIAL REGISTRATION: This study was registered in the UMIN Clinical Trials Registry (Registry ID UMIN: 000031982).

Long-Term Changes in Sagittal Balance After Microsurgical Decompression of Lumbar Spinal Canal Stenosis in Elderly Patients: A Follow-Up Study for 5-Years After Surgery.

OBJECTIVE: The purpose of this study is to investigate long-term changes in spinal sagittal balance after microsurgical decompression in lumbar canal stenosis (LCS). METHODS: Fifty-two patients who underwent microsurgical decompression for symptomatic single level L4/5 spinal canal stenosis at our hospital were included in the study. All patients had standing full spine radiographs taken preoperatively, 1 year postoperatively, and 5 years postoperatively. Spinal parameters including sagittal balance were measured from the obtained images. First, preoperative parameters were compared with 50 age-matched asymptomatic volunteers. Next, the parameters before and after surgery were compared to examine long-term changes. RESULTS: Sagittal vertical axis (SVA) was significantly increased in the LCS cases compared to the volunteers (P = 0.03). Postoperative lumbar lordosis (LL) was significantly increased (P = 0.03). Postoperative mean SVA decreased but the difference was not significant (P = 0.12). Although there was no correlation between preoperative parameters and the Japanese Orthopedic Association score, postoperative pelvic incidence (PI)-LL and pelvic tilt changes correlated with changes in Japanese Orthopedic Association score (PI-LL; P = 0.0001, pelvic tilt; P = 0.04). However, after 5 years of surgery, LL decreased and PI-LL increased (LL; P = 0.08, PI-LL; P = 0.03). Sagittal balance began to deteriorate but was not significant (P = 0.31). At 5 years postoperatively, 18 of 52 patients (34.6%) were found to have L3/4 adjacent segment disease. Cases with adjacent segment disease showed significantly worse SVA and PI-LL (SVA; P = 0.01, PI-LL; P < 0.01). CONCLUSIONS: In LCS, lumbar kyphosis improves and sagittal balance tends to improve after microsurgical decompression. However, after 5 years, adjacent intervertebral degeneration occurs more frequently and sagittal balance begins to deteriorate in about one third of cases.

Tiotropium for refractory cough in asthma via cough reflex sensitivity: A randomized, parallel, open-label trial.

BACKGROUND: We previously reported in an uncontrolled study that tiotropium alleviated chronic cough in asthma refractory to inhaled corticosteroids and long-acting ß2 agonists (ICS/LABA) by modulating capsaicin cough reflex sensitivity (C-CRS). OBJECTIVE: We sought to determine the antitussive effects of tiotropium for refractory cough in asthma in a randomized, parallel, open-label trial. METHODS: A total of 58 patients with asthma having chronic cough refractory to ICS/LABA were randomized in a 2:1 ratio to add tiotropium 5 µg (39 patients) or theophylline 400 mg (19 patients) for 4 weeks. Patients underwent workups, including capsaicin cough challenge test and subjective measures such as cough severity visual analog scales (VAS). We adopted C5, the lowest capsaicin concentration to induce at least 5 coughs, as an index of C-CRS. We also performed a posthoc analysis to identify factors predicting tiotropium responders, who found an improvement of at least 15 mm in cough severity VAS. RESULTS: A total of 52 patients (tiotropium, 38; theophylline, 14) completed the study. Both tiotropium and theophylline significantly improved cough severity VAS and cough-specific quality of life. Tiotropium, but not theophylline, significantly increased C5, whereas pulmonary function did not change in either group. In addition, changes in cough severity VAS correlated with changes in C5 values in the tiotropium group. A posthoc analysis revealed that heightened C-CRS (C5 ≤1.22 µM) before the addition of tiotropium was an independent predictor for tiotropium responders. CONCLUSION: Tiotropium may alleviate chronic cough in asthma refractory to ICS/LABA by modulating C-CRS. Heightened C-CRS may predict responsiveness to tiotropium for refractory cough in asthma. TRIAL REGISTRATION: Clinical Trials Registry ID: UMIN000021064 (https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000024253).

Targeting the interleukin-5 pathway improves cough hypersensitivity in patients with severe uncontrolled asthma.

BACKGROUND: Capsaicin cough sensitivity (C-CS) reflects airway neuronal dysfunction and may be a significant biomarker of asthma. Although mepolizumab reduces cough in patients with severe uncontrolled asthma, it is unclear whether the cough reduction is associated with improved C-CS. OBJECTIVE: To clarify the effect of biologics on C-CS and cough-specific quality of life (QoL) in patients with severe uncontrolled asthma using our previous study cohort. METHODS: Overall, 52 consecutive patients who visited our hospital for severe uncontrolled asthma were included in the original study cohort, and 30 patients were eligible for this study. Changes in C-CS and cough-specific QoL were compared between patients treated with the anti-interleukin-5 (IL-5) pathway (n = 16) and those treated with other biologics (n = 14). The C-CS was measured as the concentration of capsaicin required to induce at least 5 coughs. RESULTS: Biologics significantly improved C-CS (P = .03). Anti-IL-5 pathway therapies significantly improved C-CS, whereas other biologics did not (P < .01 and P = .89, respectively). The C-CS improved significantly more in the anti-IL-5 pathway group than in the group treated with other biologics (P = .02). Changes in C-CS significantly correlated with improvements in cough-specific QoL in the anti-IL-5 pathway group (r = 0.58, P = .01) but not in the group treated with other biologics (r = 0.35, P = .22). CONCLUSION: Anti-IL-5 pathway therapies improve C-CS and cough-specific QoL, and targeting the IL-5 pathway may be a therapeutic strategy for cough hypersensitivity in patients with severe uncontrolled asthma.

[Three Cases of Conversion Surgery Resulted in Pathological Complete Response for Unresectable Pancreatic Cancer].

Conversion surgery(CS)post chemotherapy for unresectable pancreatic cancer is often reported recently. Although it is still controversial about adaptation of CS, it could possibly be one of the useful choices of treatment for unresectable pancreatic cancer. We report 3 cases of CS which eventually turned out to be pathological complete response.

Decreased capsaicin cough reflex sensitivity predicts hospitalisation due to COPD.

INTRODUCTION: Patients with chronic obstructive pulmonary disease (COPD) are often hospitalised due to severe acute exacerbation (AE) or community-acquired pneumonia (CAP). Previous studies revealed the association of cough reflex sensitivity with the pathophysiology of COPD and pneumonia. We hypothesised that cough reflex sensitivity may be associated with severe AE or CAP requiring hospitalisation in patients with COPD. METHODS: We prospectively recruited 68 patients with COPD between June 2018 and January 2020. Patient characteristics, lung and cardiac functions, and biomarkers, including capsaicin cough reflex sensitivity and blood eosinophil count, were evaluated at enrolment. All participants were monitored for AE or CAP requiring hospitalisation for 12 months. We determined the risk factors and ORs for hospitalisation in patients with COPD using a multivariate analysis. RESULTS: Eight patients experienced AE (n=3) or CAP (n=5) and required hospitalisation during follow-up. Patients in the hospitalisation+ group had higher modified Medical Research Council scores and blood eosinophil counts (≥300 µL) than those in the hospitalisation- group. Capsaicin cough reflex sensitivity tended to decrease in the hospitalisation+ group compared with that in the hospitalisation- group. Multivariate analysis revealed that a decreased capsaicin cough reflex and high eosinophil count (≥300 µL) were predictive risk factors for future hospitalisation due to AE-COPD or CAP. CONCLUSION: In addition to eosinophils, decreased capsaicin cough reflex sensitivity was associated with hospitalisation due to AE-COPD or CAP. Capsaicin cough reflex sensitivity in patients with COPD may play a role in the prevention of severe AE or pneumonia requiring hospitalisation. TRIAL REGISTRATION NUMBER: UMIN000032497.