A Continuum of Response Properties across the Population of Unipolar Brush Cells in the Dorsal Cochlear Nucleus.

Unipolar brush cells (UBCs) in the cerebellum and dorsal cochlear nucleus (DCN) perform temporal transformations by converting brief mossy fiber bursts into long-lasting responses. In the cerebellar UBC population, mixing inhibition with graded mGluR1-dependent excitation leads to a continuum of temporal responses. In the DCN, it has been thought that mGluR1 contributes little to mossy fiber responses and that there are distinct excitatory and inhibitory UBC subtypes. Here, we investigate UBC response properties using noninvasive cell-attached recordings in the DCN of mice of either sex. We find a continuum of responses to mossy fiber bursts ranging from 100 ms excitation to initial inhibition followed by several seconds of excitation to inhibition lasting for hundreds of milliseconds. Pharmacological interrogation reveals excitatory responses are primarily mediated by mGluR1 Thus, UBCs in both the DCN and cerebellum rely on mGluR1 and have a continuum of response durations. The continuum of responses in the DCN may allow more flexible and efficient temporal processing than can be achieved with distinct excitatory and inhibitory populations.SIGNIFICANCE STATEMENT UBCs are specialized excitatory interneurons in cerebellar-like structures that greatly prolong the temporal responses of mossy fiber inputs. They are thought to help cancel out self-generated signals. In the DCN, the prevailing view was that there are two distinct ON and OFF subtypes of UBCs. Here, we show that instead the UBC population has a continuum of response properties. Many cells show suppression and excitation consecutively, and the response durations vary considerably. mGluR1s are crucial in generating a continuum of responses. To understand how UBCs contribute to temporal processing, it is essential to consider the continuous variations of UBC responses, which have advantages over just having opposing ON/OFF subtypes of UBCs.

Elevated Cancer-Associated Hyaluronan Correlates With Diagnosis and Lymph Node Metastasis of Papillary Thyroid Cancer.

The glycosaminoglycan hyaluronan (HA) plays an important role in tumor progression. However, its biological and clinical significance in papillary thyroid cancer (PTC) remains unknown. Immunohistochemistry was performed to examine HA expression in tissues from PTC patients. Two PTC cell lines were treated with HA synthesized inhibitor against HA production to assess its function. Serum HA levels from 107 PTC patients, 30 Hashimoto thyroiditis patients, and 45 normal controls (NC) were measured by chemiluminescence immunoassay. HA levels in fine needle aspiration (FNA) washouts obtained from thyroid nodules and lymph nodes (LNs) were measured by chemiluminescence immunoassay. Area under the curve (AUC) was computed to evaluate HA's clinical value. HA was highly expressed in PTC. Reducing HA production significantly inhibited PTC cell proliferation and invasion. Importantly, serum HA levels in PTC were significantly higher than those in NCs and Hashimoto thyroiditis and allowed distinguishing of thyroid cancers from NCs with high accuracy (AUC = 0.782). Moreover, elevated serum HA levels in PTC correlate with LN metastasis. HA levels in FNA washouts from PTC patients were significantly higher than those in benign controls, with a high AUC value (0.8644) for distinguishing PTC from benign controls. Furthermore, HA levels in FNA washouts from metastatic LN were significantly higher than those in nonmetastatic LN, with a high AUC value (0.8007) for distinguishing metastatic LNs from nonmetastatic LNs. HA levels in serum and FNA washout exhibited a potential significance for PTC diagnosis and an indicator for LN metastasis in patients with PTC.

Performance of CT With Adrenal-Washout Protocol in Heterogeneous Adrenal Nodules: A Multiinstitutional Study.

BACKGROUND. CT with adrenal-washout protocol (hereafter, adrenal-protocol CT) is commonly performed to distinguish adrenal adenomas from other adrenal tumors. However, the technique's utility among heterogeneous nodules is not well established, and the optimal method for placing ROIs in heterogeneous nodules is not clearly defined. OBJECTIVE. The purpose of our study was to determine the diagnostic performance of adrenal-protocol CT to distinguish adenomas from nonadenomas among heterogeneous adrenal nodules and to compare this performance among different methods for ROI placement. METHODS. This retrospective study included 164 patients (mean age, 59.1 years; 61 men, 103 women) with a total of 164 heterogeneous adrenal nodules evaluated using adrenal-protocol CT at seven institutions. All nodules had an available pathologic reference standard. A single investigator at each institution evaluated the CT images. ROIs were placed on portal venous phase images using four ROI methods: standard ROI, which refers to a single large ROI in the nodule's center; high ROI, a single ROI on the nodule's highest-attenuation area; low ROI, a single ROI the on nodule's lowest-attenuation area; and average ROI, the mean of the three ROIs on the nodule's superior, middle, and inferior thirds using the approach for the standard ROI. ROIs were then placed in identical locations on unenhanced and delayed phase images. Absolute washout was determined for all methods. RESULTS. The nodules comprised 82 adenomas and 82 nonadenomas (36 pheochromocytomas, 20 metastases, 12 adrenocortical carcinomas, and 14 nodules with other pathologies). The mean nodule size was 4.5 ± 2.8 (SD) cm (range, 1.6-23.0 cm). Unenhanced CT attenuation of 10 HU or less exhibited sensitivity and specificity for adenoma of 22.0% and 96.3% for standard-ROI, 11.0% and 98.8% for high-ROI, 58.5% and 84.1% for low-ROI, and 30.5% and 97.6% for average-ROI methods. Adrenal-protocol CT overall (unenhanced attenuation ≤ 10 HU or absolute washout of ≥ 60%) exhibited sensitivity and specificity for adenoma of 57.3% and 84.1% for the standard-ROI method, 63.4% and 51.2% for the high-ROI method, 68.3% and 62.2% for the low-ROI method, and 59.8% and 85.4% for the average-ROI method. CONCLUSION. Adrenal-protocol CT has poor diagnostic performance for distinguishing adenomas from nonadenomas among heterogeneous adrenal nodules regardless of the method used for ROI placement. CLINICAL IMPACT. Adrenal-protocol CT has limited utility in the evaluation of heterogeneous adrenal nodules.

Detailed characterization and impact of small airway dysfunction in school-age asthma.

BACKGROUND: Small airway dysfunction (SAD) is increasingly recognized as an important feature of pediatric asthma yet typically relies on spirometry-derived FEF25-75 to detect its presence. Multiple breath washout (MBW) and oscillometry potentially offer improved sensitivity for SAD detection, but their utility in comparison to FEF25-75, and correlations with clinical outcomes remains unclear for school-age asthma. We investigated SAD occurrence using these techniques, between-test correlation and links to clinical outcomes in 57 asthmatic children aged 8-18 years. METHODS: MBW and spirometry abnormality were defined as z-scores above/below ± 1.96, generating MBW reference equations from contemporaneous controls (n = 69). Abnormal oscillometry was defined as > 97.5th percentile, also from contemporaneous controls (n = 146). Individuals with abnormal FEF25-75, MBW, or oscillometry were considered to have SAD. RESULTS: Using these limits of normal, SAD was present on oscillometry in 63% (resistance at 5-20 Hz; R5-R20; >97.5th percentile), on MBW in 54% (Scond; z-scores> +1.96) and in spirometry FEF25-75 in 44% of participants (z-scores< -1.96). SAD, defined by oscillometry and/or MBW abnormality, occurred in 77%. Among those with abnormal R5-R20, Scond was abnormal in 71%. Correlations indicated both R5-R20 and Scond were linked to asthma medication burden, baseline FEV1 and reversibility. Additionally, Scond correlated with FENO and magnitude of bronchial hyper-responsiveness. SAD, detected by oscillometry and/or MBW, occurred in almost 80% of school-aged asthmatic children, surpassing FEF25-75 detection rates. CONCLUSIONS: Discordant oscillometry and MBW abnormality suggests they reflect different aspects of SAD, serving as complementary tools. Key asthma clinical features, like reversibility, had stronger correlation with MBW-derived Scond than oscillometry-derived R5-R20.

Ventilation heterogeneity is increased in adults exposed to coal mine fire-related PM2.5.

BACKGROUND AND OBJECTIVES: The Hazelwood Health Study was set up to study long-term health effects of a mine fire that blanketed residents of the Latrobe Valley with smoke for 45 days in 2014. The Respiratory Stream specifically assessed the impact of fine particulate matter <2.5 µm diameter (PM2.5) exposure from mine fire smoke on lung health. The multiple breath nitrogen washout (MBW) test assesses ventilation heterogeneity, which may detect sub-clinical airways dysfunction not identified using standard tests such as spirometry. This analysis assessed the association of PM2.5 exposure with measures of ventilation heterogeneity. METHODS: Exposed (Morwell) and unexposed (Sale) participants were recruited 3.5-4 years after the fire from those who had participated in an Adult Survey. MBW was performed to measure lung clearance index (LCI), functional residual capacity (FRC), acinar (Sacin) and conductive (Scond) ventilation heterogeneity. PM2.5 exposure was estimated with emission and chemical transport models. Multivariable linear regression models were fitted controlling for confounders. RESULTS: We recruited 519 participants. MBW tests were conducted on 504 participants with 479 acceptable test results (40% male; 313 exposed, 166 unexposed). Exposure to mine fire-related PM2.5 was associated with increasing Scond (ß = 1.57/kL, 95%CI: 0.20-2.95, p = 0.025), which was comparable to the estimated effect on Scond of 4.7 years of aging. No other MBW outcomes were statistically different. CONCLUSION: Increasing exposure to PM2.5 was associated with increased ventilation heterogeneity in the conductive region of the lungs 4 years after the event.

Respiratory effects of pressure support ventilation in spontaneously breathing patients under anaesthesia: Randomised controlled trial.

BACKGROUND: Lung volume loss is a major risk factor for postoperative respiratory complications after general anaesthesia and mechanical ventilation. We hypothesise that spontaneous breathing without pressure support may enhance the risk for atelectasis development. Therefore, we aimed at characterising whether pressure support prevents changes in lung function in patients breathing spontaneously through laryngeal mask airway. METHODS: In this randomised controlled trial, adult female patients scheduled for elective gynaecological surgery in lithotomy position were randomly assigned to the continuous spontaneous breathing group (CSB, n = 20) or to the pressure support ventilation group (PSV, n = 20) in a tertiary university hospital. Lung function measurements were carried out before anaesthesia and 1 h postoperatively by a researcher blinded to the group allocation. Lung clearance index calculated from end-expiratory lung volume turnovers as primary outcome variable was assessed by the multiple-breath nitrogen washout technique (MBW). Respiratory mechanics were measured by forced oscillations to assess parameters reflecting the small airway function and respiratory tissue stiffness. RESULTS: MBW was successfully completed in 18 patients in both CSB and PSV groups. The decrease in end-expiratory lung volume was more pronounced in the CSB than that in the PSV group (16.6 ± 6.6 [95% CI] % vs. 7.6 ± 11.1%, p = .0259), with no significant difference in the relative changes of the lung clearance index (-0.035 ± 7.1% vs. -0.18 ± 6.6%, p = .963). The postoperative changes in small airway function and respiratory tissue stiffness were significantly lower in the PSV than in the CSB group (p < .05 for both). CONCLUSIONS: These results suggest that pressure support ventilation protects against postoperative lung-volume loss without affecting ventilation inhomogeneity in spontaneously breathing patients with increased risk for atelectasis development. TRIAL REGISTRATION: NCT02986269.

Plasticity of Individual Lung Function States from Childhood to Adulthood.

Rationale: Recent evidence highlights the importance of optimal lung development during childhood for health throughout life. Objectives: To explore the plasticity of individual lung function states during childhood. Methods: Prebronchodilator FEV1 z-scores determined at age 8, 16, and 24 years in the Swedish population-based birth cohort BAMSE (Swedish abbreviation for Child [Barn], Allergy, Milieu, Stockholm, Epidemiological study) (N = 3,069) were used. An unbiased, data-driven dependent mixture model was applied to explore lung function states and individual state chains. Lung function catch-up was defined as participants moving from low or very low states to normal or high or very high states, and growth failure as moving from normal or high or very high states to low or very low states. At 24 years, we compared respiratory symptoms, small airway function (multiple-breath washout), and circulating inflammatory protein levels, by using proteomics, across states. Models were replicated in the independent Dutch population-based PIAMA (Prevention and Incidence of Asthma and Mite Allergy) cohort. Measurements and Main Results: Five lung function states were identified in BAMSE. Lung function catch-up and growth failure were observed in 74 (14.5%) BAMSE participants with low or very low states and 36 (2.4%) participants with normal or high or very high states, respectively. The occurrence of catch-up and growth failure was replicated in PIAMA. Early-life risk factors were cumulatively associated with the very low state, as well as with catch-up (inverse association) and growth failure. The very low state as well as growth failure were associated with respiratory symptoms, airflow limitation, and small airway dysfunction at adulthood. Proteomics identified IL-6 and CXCL10 (C-X-C motif chemokine 10) as potential biomarkers of impaired lung function development. Conclusions: Individual lung function states during childhood are plastic, including catch-up and growth failure.

Evaluation of qualitative and quantitative imaging features of hepatic hemangiomas with and without pseudo-washout sign on gadoxetic acid-enhanced MRI: a descriptive and comparative study.

BACKGROUND: Hepatic hemangiomas are the most common benign liver tumors. It is important to know the imaging features of hemangiomas on gadoxetic acid (GA)-enhanced magnetic resonance imaging (MRI). PURPOSE: To evaluate the qualitative and quantitative imaging features of hemangiomas on GA-enhanced MRI, and to compare imaging features of hemangiomas with and without pseudo-washout sign (PWS). MATERIAL AND METHODS: We retrospectively included 93 cases of hemangioma that underwent GA-enhanced MRI. The presence of an enhancement pattern in the arterial phase (AP) and PWSs in the transitional phase (TP) were evaluated. Signal-to-norm ratios (SINorm) of hemangiomas, liver parenchyma, and portal vein (PV) as well as contrast-to-norm ratio (CNorm) were assessed. Additionally, hemangiomas with and without PWSs were defined as two separate subgroups, and imaging features were compared. RESULTS: Of the 93 cases of hemangiomas, 49 (52.6%) had PWSs in the TP. The mean SINorms of hemangiomas showed the highest value in the AP (P < 0.05). The mean CNorms showed positive values in the AP, and gradually decreased (P < 0.05). Hemangiomas with PWSs were significantly rapidly enhanced and smaller in size (P < 0.05), and the mean SINorms was lower in the TP (P = 0.023). While the mean CNorms showed a significant difference in the AP between subgroups (P < 0.001), the enhancement pattern was equal to that of the PV. CONCLUSION: When evaluating GA-enhanced MRI, radiologists should utilize quantitative measures in addition to qualitative assessment and should be aware that SI matching with PV in all phases can be a distinguishing finding in the diagnosis of hemangioma.

Fine needle aspiration biopsy of parathyroid; is it meaningful? A cytologic study of 81 cases with histological and clinical correlations.

BACKGROUND: Recognizing the parathyroid gland and distinguishing the parathyroid from thyroid lesions in fine needle aspiration (FNA) is challenging. This study aimed to identify cytomorphologic features suggestive of parathyroid origin and to assess the utility of cytopathology in conjunction with ancillary tests in the identification of parathyroid glands. MATERIALS AND METHODS: Ultrasound (US) guided FNA of parathyroid gland and lesions in 81 patients were reviewed concerning clinical history and correlated to histopathologic findings in available cases. FNA smears were evaluated for cellularity, architectural patterns, cellular and nuclear features, and background of the smears. In 78 cases, FNA was supplemented by a measurement of parathormone (PTH) levels in the needle washout fluid (FNA-PTH assay) and/or GATA3/PTH/chromogranin-A immunostainings. RESULTS: Sixty-four cases were diagnosed cytologically as parathyroid lesions in conjunction with FNA-PTH assay and/or immunocytochemical examinations. In an additional nine cases, a diagnosis of parathyroid lesions was rendered after repeated FNA with FNA-PTH assay. The histolopathologic diagnosis of surgically excised cases (n = 75) included parathyroid adenoma (60 cases), atypical parathyroid adenoma (4 cases), parathyroid hyperplasia (10 cases), and parathyroid carcinoma (1 case). Major cytological findings of parathyroid tissue included high cellularity, scattered naked nuclei, cribriform and three-dimensional clusters, stippled chromatin, and oxyphilic cytoplasm while papillary pattern or colloid-like material was identified in three cases respectively. No nuclear grooves or inclusions were seen in any case. CONCLUSIONS: High cellularity scattered naked nuclei, cribriform and three-dimensional patterns, stippled chromatin and oxyphilic cytoplasm are cytomorphologic features that favour parathyroid origin. A combination of these features with FNA-PTH assay and/or GATA3, PTH, and chromogranin-A immunostainings on cytologic specimens aid in the identification of parathyroid glands and the distinguishing of parathyroid from thyroid lesions.

Evaluation of Washout Periods After Dorsal Root Ganglion Stimulation Trial.

OBJECTIVE: Dorsal root ganglion stimulation (DRG-S) is a novel therapy to treat chronic pain. It has shown efficacy when delivered intermittently, suggesting a delayed washout effect exists. To measure the washout period, and to determine whether there are differences in washout times among different types of treated pain, we measured the time for pain to return at the end of the patients' one-week DRG stimulation trials. MATERIALS AND METHODS: Patients who completed a successful DRG-S trial were included. The times until 25% (t25) and 90% (t90) of baseline pain level returned were recorded. The patients were divided into neuropathic, nociceptive, and mixed pain groups for subgroup comparison. t25 and t90 were plotted in the entire cohort and subgroups using reverse Kaplan-Meier plots (failure curves) and compared using a log-rank test. RESULTS: In total, 29 consecutive patients were included. Median t25 and t90 times were 7.1 and 19.5 hours, respectively. Median (interquartile range) times were longest for the nociceptive pain group (n = 17) and shortest for the neuropathic pain group (n = 6), with the mixed-pain group (n = 6) in between (t25: 7.1 [1.7-19.4], 3.40 [1.4-8.4], and 5.7 [0.8-17.6]; t90, 22.0 [10.7-71.0], 7.6 [3.6-19.8], and 20.9 [14.2-31.2], respectively). t90 times differed significantly by pain type (p = 0.040). CONCLUSIONS: This study showed a prolonged washout period after cessation of DRG-S therapy. Washout times vary according to pain type. The observed effects are possibly due to long-term depression of pain signaling and could allow the implementation of alternative stimulation strategies with DRG-S. Further investigations evaluating DRG-S washout times are warranted.

Diagnostic value and cost-effectiveness of FNA-CT versus FNAC for medullary thyroid carcinoma.

OBJECTIVE: To evaluate the diagnostic performance and cost-effectiveness of calcitonin assays in fine-needle aspiration washout fluid (FNA-CT) compared to fine-needle aspiration cytology (FNAC) for medullary thyroid carcinoma (MTC). METHODS: A total of 27,404 patients from three medical centres between January 2020 and May 2022 were screened for serum calcitonin (sCT). Of whom, 223 patients met endpoints and were enroled for analyses. Based on sCT levels, patients were divided into two groups (group 1: 10 pg/ml< sCT ≤100 pg/ml and group 2: sCT > 100 pg/ml). The diagnostic performance and cost-effectiveness of FNA-CT and FNAC were compared. RESULTS: Most patients (N = 25,228; 92.1%) with thyroid nodules had normal sCT levels. In group 1, 24 and 167 nodules were diagnosed as MTC and non-MTC lesions, respectively. FNA-CT showed better performance in diagnosing MTC than FNAC in terms of sensitivity (100.0% vs. 58.3%), negative predictive value (100.0% vs. 94.3%), and overall accuracy (100.0% vs. 94.7%). In group 2, 67 and 7 nodules were diagnosed as MTC and non-MTC lesions, respectively. The diagnostic performance of FNA-CT was superior to FNAC in terms of sensitivity (100.0% vs. 64.2%), negative predictive value (100.0% vs. 22.6%), and overall accuracy (100.0% vs. 67.6%). Furthermore, analysis from the decision tree model showed that FNA-CT was a cost-effective tool for diagnosing MTC lesions. CONCLUSIONS: FNA-CT can serve as an auxiliary and cost-effective approach for patients with indeterminate sCT levels to detect occult MTC lesions. FNA-CT can be recommended for patients with sCT >100 pg/ml to overcome the high false-negative rate of FNAC.

Intra- and Inter-visit Repeatability of 129 Xenon Multiple-Breath Washout MRI in Children With Stable Cystic Fibrosis Lung Disease.

BACKGROUND: Multiple-breath washout (MBW) 129 Xe MRI (MBW Xe-MRI) is a promising technique for following pediatric cystic fibrosis (CF) lung disease progression. However, its repeatability in stable CF needs to be established to use it as an outcome measure for novel therapies. PURPOSE: To assess intravisit and intervisit repeatability of MBW Xe-MRI in healthy and CF children. STUDY TYPE: Prospective, longitudinal cohort study. SUBJECTS: A total of 18 pediatric subjects (7 healthy, 11 CF). FIELD STRENGTH/SEQUENCE: A 3 T/2D coronal hyperpolarized (HP) 129 Xe images using GRE sequence. ASSESSMENT: All subjects completed MBW Xe-MRI, pulmonary function tests (PFTs) (spirometry, nitrogen [N2 ] MBW for lung clearance index [LCI]) and ventilation defect percent (VDP) at baseline (visit 1) and 1-month after. Fractional ventilation (FV), coefficient of variation (CoVFV ) maps were calculated from MBW Xe-MRI data acquired between intervening air washout breaths performed after an initial xenon breath-hold. Skewness of FV and CoVFV map distributions was also assessed. STATISTICAL TESTS: Repeatability: intraclass correlation coefficients (ICC), within-subject coefficient of variation (CV%), repeatability coefficient (CR). Agreement: Bland-Altman. For correlations between MBW Xe-MRI, VDP and PFTs: Spearman's correlation. Significance threshold: P < 0.05. RESULTS: For FV, intravisit median [IQR] ICC was high in both healthy (0.94 [0.48, 0.99]) and CF (0.83 [0.04, 0.97]) subjects. CoVFV also had good intravisit ICC in healthy (0.92 [0.42, 0.99]) and CF (0.79 [0.02, 0.96]) subjects. Similarly, for FV, intervisit ICC was high in health (0.94 [0.68, 0.99]) and CF (0.89 [0.61, 0.97]). CoVFV also had good intervisit ICC in health (0.92 [0.42, 0.99]) and CF (0.78 [0.26, 0.94]). FV had better intervisit repeatability than VDP. CoVFV correlated significantly with LCI (R = 0.56). Skewness of FV distributions significantly distinguished between cohorts at baseline. DATA CONCLUSION: MBW Xe-MRI had high intravisit and intervisit repeatability in healthy and stable CF subjects. CoVFV correlated with LCI, suggesting the importance of ventilation heterogeneity to early CF. EVIDENCE LEVEL: 1. TECHNICAL EFFICACY: Stage 2.

The impact of antenatal and postnatal indoor air pollution or tobacco smoke exposure on lung function at 3 years in an African birth cohort.

BACKGROUND AND OBJECTIVE: Indoor air pollution (IAP) and tobacco smoke exposure (ETS) are global health concerns contributing to the burden of childhood respiratory disease. Studies assessing the effects of IAP and ETS in preschool children are limited. We assessed the impact of antenatal and postnatal IAP and ETS exposure on lung function in a South African birth cohort, the Drakenstein Child Health Study. METHODS: Antenatally enrolled mother-child pairs were followed from birth. Lung function measurements (oscillometry, multiple breath washout and tidal breathing) were performed at 6 weeks and 3 years. Quantitative antenatal and postnatal IAP (particulate matter [PM10 ], volatile organic compounds [VOC]) and ETS exposures were measured. Linear regression models explored the effects of antenatal and postnatal exposures on lung function at 3 years. RESULTS: Five hundred eighty-four children had successful lung function testing, mean (SD) age of 37.3 (0.7) months. Exposure to antenatal PM10 was associated with a decreased lung clearance index (p < 0.01) and postnatally an increase in the difference between resistance at end expiration (ReE) and inspiration (p = 0.05) and decrease in tidal volume (p = 0.06). Exposure to antenatal VOC was associated with an increase in functional residual capacity (p = 0.04) and a decrease in time of expiration over total breath time (tE /tTOT ) (p = 0.03) and postnatally an increase in respiratory rate (p = 0.05). High ETS exposure postnatally was associated with an increase in ReE (p = 0.03). CONCLUSION: Antenatal and postnatal IAP and ETS exposures were associated with impairment in lung function at 3 years. Strengthened efforts to reduce IAP and ETS exposure are needed.

Effects of Elexacaftor/Tezacaftor/Ivacaftor Therapy on Lung Clearance Index and Magnetic Resonance Imaging in Patients with Cystic Fibrosis and One or Two F508del Alleles.

Rationale: We recently demonstrated that triple-combination CFTR (cystic fibrosis transmembrane conductance regulator) modulator therapy with elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) improves CFTR function in airway and intestinal epithelia to 40-50% of normal in patients with cystic fibrosis (CF) with one or two F508del alleles. In previous studies, this improvement of CFTR function was shown to improve clinical outcomes; however, effects on the lung clearance index (LCI) determined by multiple-breath washout and abnormalities in lung morphology and perfusion detected by magnetic resonance imaging (MRI) have not been studied. Objectives: To examine the effect of ELX/TEZ/IVA on LCI and lung MRI scores in patients with CF and one or two F508del alleles aged ⩾12 years. Methods: This prospective, observational, multicenter, postapproval study assessed LCI and lung MRI scores before and 8-16 weeks after initiation of ELX/TEZ/IVA. Measurements and Main Results: A total of 91 patients with CF, including 45 heterozygous for F508del and a minimal function mutation (MF) and 46 homozygous for F508del, were enrolled in this study. Treatment with ELX/TEZ/IVA improved LCI in F508del/MF (-2.4; interquartile range [IQR], -3.7 to -1.1; P < 0.001) and F508del homozygous (-1.4; IQR, -2.4 to -0.4; P < 0.001) patients. Furthermore, ELX/TEZ/IVA improved the MRI global score in F508del/MF (-6.0; IQR, -11.0 to -1.3; P < 0.001) and F508del homozygous (-6.5; IQR, -11.0 to -1.3; P < 0.001) patients. Conclusions: Our data demonstrate that improvement of CFTR function by ELX/TEZ/IVA improves lung ventilation and abnormalities in lung morphology, including airway mucus plugging and wall thickening, in adolescent and adult patients with CF and one or two F508del alleles in a real-world, postapproval setting. Clinical trial registered with www.clinicaltrials.gov (NCT04732910).

Rebounds of sevoflurane concentration during simulated trigger-free pediatric and adult anesthesia.

BACKGROUND: In trigger-free anesthesia a volatile anesthetic concentration of 5 parts per million (ppm) should not be exceeded. According to European Malignant Hyperthermia Group (EMHG) guideline, this may be achieved by removing the vapor, changing the anesthetic breathing circuit and renewing the soda lime canister followed by flushing with O2 or air for a workstation specific time. Reduction of the fresh gas flow (FGF) or stand-by modes are known to cause rebound effects. In this study, simulated trigger-free pediatric and adult ventilation was carried out on test lungs including ventilation maneuvers commonly used in clinical practice. The goal of this study was to evaluate whether rebounds of sevoflurane develop during trigger-free anesthesia. METHODS: A Dräger® Primus® was contaminated with decreasing concentrations of sevoflurane for 120 min. Then, the machine was prepared for trigger-free anesthesia according to EMHG guideline by changing recommended parts and flushing the breathing circuits using 10 or 18 l⋅min- 1 FGF. The machine was neither switched off after preparation nor was FGF reduced. Simulated trigger-free ventilation was performed with volume-controlled ventilation (VCV) and pressure-controlled ventilation (PCV) including various ventilation maneuvers like pressure support ventilation (PSV), apnea, decreased lung compliance (DLC), recruitment maneuvers, prolonged expiration and manual ventilation (MV). A high-resolution ion mobility spectrometer with gas chromatographic pre-separation was used to measure sevoflurane in the ventilation gas mixture in a 20 s interval. RESULTS: Immediately after start of simulated anesthesia, there was an initial peak of 11-18 ppm sevoflurane in all experiments. The concentration dropped below 5 ppm after 2-3 min during adult and 4-18 min during pediatric ventilation. Other rebounds of sevoflurane > 5 ppm occurred after apnea, DLC and PSV. MV resulted in a decrease of sevoflurane < 5 ppm within 1 min. CONCLUSION: This study shows that after guideline-compliant preparation for trigger-free ventilation anesthetic machines may develop rebounds of sevoflurane > 5 ppm during typical maneuvers used in clinical practice. The changes in rate and direction of internal gas flow during different ventilation modes and maneuvers are possible explanations. Therefore, manufacturers should provide machine-specific washout protocols or emphasize the use of active charcoal filters (ACF) for trigger-free anesthesia.

Surgical treatment for BPH refractory to medication: robotic water jet ablation vs. TURP functional outcomes from two FDA clinical trials.

INTRODUCTION: A common indication for benign prostate hyperplasia (BPH) therapies is failure to improve with medical therapy. However, pivotal Federal Drug Administration (FDA) registered randomized clinical trials (RCTs) for minimally invasive surgical therapies (MISTs) are designed to be compared to either sham or placebo while off medical therapy at baseline, and as an alternative to medical therapy. There are few if any RCTs reporting the MISTS efficacy in patients with true medical therapy failure. We report on the efficacy of robotic water jet ablation therapy (RWT) and TURP in patients who have failed to improve with medical therapy. MATERIALS AND METHODS: Data was obtained from the WATER and WATER II clinical trials. Both clinical trials did not implement a drug washout period. Only patients with reported BPH medical therapy such as alpha-blockers (AB) and 5-alpha-reductase inhibitors (5-ARIs) usage were included. Functional outcomes as post-void residual volume (PVR), peak urinary flow rate (Qmax), internal prostate symptom score (IPSS), and quality of life score (QoL) were analyzed. RESULTS: AB and/or 5-ARIs usage at baseline were reported in 146 and 39 patients who underwent RWT (prostate sizes up to 150 cc) and transurethral resection of the prostate (TURP, prostate sizes up to 80 cc) respectively. Baseline median (IQR) IPSS, QoL, Qmax and PVR were 24 (18,28), 5 (4,5), 8.9 (6.4,11.5), and 95 (36,172), respectively. Functional outcomes did not statistically differ between Aquablation and TURP at baseline and at 36-month. In cohort of true medical failure, both RWT and TURP demonstrated group statistical improvements in PVR, Qmax, IPSS, and QoL at 36-month compared to baseline. CONCLUSIONS: RWT and TURP are effective BPH therapy in patients who truly failed medical therapy, and RWT demonstrated this in a much broader prostate size range.

Does short-term antipsychotic discontinuation of up to 3 weeks worsen symptoms in acute schizophrenia? A pooled analysis of placebo washout data.

AIM: This study aimed to examine symptom changes during short-term discontinuation of antipsychotics up to 3 weeks including the placebo washout phase in acute schizophrenia. METHODS: The data from three double-blind, randomized, controlled trials comparing lurasidone versus placebo in patients with acute exacerbation of schizophrenia were analyzed. Symptom severity was assessed using the Positive and Negative Syndrome Scale (PANSS) total and the Clinical Global Impression-Severity scale (CGI-S) scores. The scores before and after the antipsychotic discontinuation phase were compared, and factors associated with score changes were explored. RESULTS: Among 2154 patients participating in the trials, 600 who received antipsychotic monotherapy and completed the antipsychotic discontinuation phase were included in the analysis. No patients received clozapine. The mean duration of the discontinuation phase was 5.9 ± 2.5 days. The PANSS total and CGI-S scores significantly changed from 94.0 ± 9.5 to 95.4 ± 10.5 (P < 0.001) and from 4.9 ± 0.6 to 4.9 ± 0.7 (P = 0.041), respectively, during this phase; however, the absolute difference was minimal. The score changes were not associated with the type or dose of prior antipsychotics, or the duration or strategy (abrupt vs gradual) of antipsychotic discontinuation. CONCLUSIONS: Symptoms may not worsen to a clinically meaningful degree after short-term discontinuation of non-clozapine antipsychotics up to 3 weeks in patients with acute exacerbation of schizophrenia, suggesting that antipsychotic efficacy persists at least several days after discontinuation. This finding supports once-daily dosing regimen of antipsychotics and abrupt antipsychotic discontinuation when switching to another antipsychotic.

Statistical methods for handling missing data to align with treatment policy strategy.

The International Council for Harmonization (ICH) E9(R1) addendum recommends choosing an appropriate estimand based on the study objectives in advance of trial design. One defining attribute of an estimand is the intercurrent event, specifically what is considered an intercurrent event and how it should be handled. The primary objective of a clinical study is usually to assess a product's effectiveness and safety based on the planned treatment regimen instead of the actual treatment received. The estimand using the treatment policy strategy, which collects and analyzes data regardless of the occurrence of intercurrent events, is usually utilized. In this article, we explain how missing data can be handled using the treatment policy strategy from the authors' viewpoint in connection with antihyperglycemic product development programs. The article discusses five statistical methods to impute missing data occurring after intercurrent events. All five methods are applied within the framework of the treatment policy strategy. The article compares the five methods via Markov Chain Monte Carlo simulations and showcases how three of these five methods have been applied to estimate the treatment effects published in the labels for three antihyperglycemic agents currently on the market.

Diagnostic accuracy of peripheral lung function measurements in paediatric asthma control assessment: a pilot study.

Introduction: Recent studies have indicated the significance of the peripheral airways in asthma control. Methods estimating airway resistance, air trapping, and ventilation inhomogeneity are useful for assessing this area of the lung and have proven utility in the evaluation of asthma; however, it is unclear which method is most effective at characterising uncontrolled asthma. Aim: To evaluate the diagnostic accuracy of various peripheral airway function measurements in the assessment of asthma control in children. Material and methods: Children with controlled (n = 35) and uncontrolled (n = 29) asthma performed a sequence of pulmonary function tests (i.e. spirometry, body plethysmography, oscillometry, nitrogen washout test, and exhaled nitric oxide). The diagnostic accuracy of each peripheral airway measure was evaluated by an area under the receiver operating characteristic curve (AUC). Results: Most peripheral airway parameters were significantly increased in children with uncontrolled asthma compared with children with controlled asthma. The measures with the highest diagnostic accuracy for asthma control were lung clearance index (LCI) (AUC = 0.76), with high specificity (0.97) and modest sensitivity (0.46), acinar ventilation heterogeneity (Sacin) (AUC = 0.73), with high sensitivity (0.85) and modest specificity (0.54), and resonance frequency (Fres) (AUC= 0.74), with perfect specificity (1.0) but low sensitivity (0.38). Conclusions: LCI, Sacin and Fres had the highest discriminative capacity for distinguishing children with controlled and uncontrolled asthma among all evaluated peripheral airways measures. Discrepancies in the performance (i.e. sensitivity and specificity) of each parameter suggest that a combination may be most effective in determining asthma control status.

Persistence of adaptation following visuomotor training.

Retention tests conducted after sensorimotor adaptation frequently exhibit a rapid return to baseline performance once the altered sensory feedback is removed. This so-called washout of learning stands in contrast with other demonstrations of retention, such as savings on re-learning and anterograde interference effects of initial learning on new learning. In the present study, we tested the hypothesis that washout occurs when there is a detectable discrepancy in retention tests between visual information on the target position and somatosensory information on the position of the limb. Participants were tested following adaptation to gradually rotated visual feedback (15° or 30°). Two different types of targets were used for retention testing, a point target in which a perceptual mismatch is possible, and an arc-target that eliminated the mismatch. It was found that, except when point targets were used, retention test movements were stable throughout aftereffect trials, indicating little loss of information. Substantial washout was only observed in tests with a single point target, following adaptation to a large amplitude 30° rotation. In control studies designed to minimize the use of explicit strategies during learning, we observed similar patterns of decay when participants moved to point targets that suggests that the effects observed here relate primarily to implicit learning. The results suggest that washout in aftereffect trials following visuomotor adaptation is due to a detectable mismatch between vision and somatosensation. When the mismatch is removed experimentally, there is little evidence of loss of information.NEW & NOTEWORTHY Aftereffects following sensorimotor adaptation are important because they bear on the understanding of the mechanisms that subserve forgetting. We present evidence that information loss previously reported during retention testing occurs only when there is a detectable discrepancy between vision and somatosensation and, if this mismatch is removed, the persistence of adaptation is observed. This suggests that washout during aftereffect trials is a consequence of the experimental design rather than a property of the memory system itself.