Median Percent Change Research Articles

Flow-resistive loading and diaphragmatic muscle function in term and preterm infants.

We aimed to assess diaphragmatic function in term and preterm infants with and without history of bronchopulmonary dysplasia (BPD), before and after the application of inspiratory flow resistive loading. Forty infants of a median (range) gestational age of 34 (25-40) weeks were studied. BPD was defined as supplemental oxygen requirement for >28 days of life. Seventeen infants were term, 17 preterm without history of BPD, and six preterm with a history of BPD. The diaphragmatic pressure-time index (PTIdi) was calculated as the mean to maximum trans-diaphragmatic pressure ratio times the inspiratory duty cycle. The PTIdi was calculated before and after the application of an inspiratory-flow resistance for 120 s. Airflow was measured by a pneumotachograph and the transdiaphragmatic pressure by a dual pressure catheter. The median (interquartile range [IQR]) pre-resistance PTIdi was higher in preterm infants without BPD (0.064 [0.050-0.077]) compared with term infants (0.052 [0.044-0.062], p = .029) and was higher in preterm infants with BPD (0.119 [0.086-0.132]) compared with a subgroup of preterm infants without BPD (0.062 [0.056-0.072], p = .004). The median (IQR) postresistance PTIdi was higher in preterm infants without BPD (0.101 [0.084-0.132]) compared with term infants (0.067 [0.055-0.083], p < .001) and was higher in preterm infants with BPD [0.201(0.172-0.272)] compared with the preterm subgroup without BPD (0.091 [0.081-0.108],p = .004). The median (IQR) percentage change of the PTIdi after the application of the resistance was higher in preterm infants without BPD (65 [51-92] %) compared with term infants (34 [20-39] %, p < .001). Preterm infants, especially those recovering from BPD, are at increased risk of diaphragmatic muscle fatigue under conditions of increased inspiratory loading.

Soluble urokinase plasminogen activator receptor and cardiotoxicity in doxorubicin-treated breast cancer patients: a prospective exploratory study

BackgroundSoluble urokinase plasminogen activator receptor is an inflammatory biomarker that may prognosticate cardiovascular outcomes. We sought to determine the associations between soluble urokinase plasminogen activator receptor and established markers of cardiotoxicity in breast cancer patients receiving doxorubicin.MethodsWe conducted a prospective cohort study of women with newly diagnosed breast cancer receiving standard-dose doxorubicin (240 mg/m2) at Rush University Medical Center and Rush Oak Park Hospital (Chicago, IL) between January 2017 and May 2019. Left ventricular ejection fraction, global longitudinal strain, and cardiac biomarkers (N-terminal prohormone B-type natriuretic peptide, troponin-I, and high-sensitivity C-reactive protein) were measured at baseline and at intervals up to 12-month follow-up after end of treatment. The associations between soluble urokinase plasminogen activator receptor and these endpoints were evaluated using multivariable mixed effects linear regression.ResultsOur study included 37 women (mean age 47.0 ± 9.3 years, 60% white) with a median baseline soluble urokinase plasminogen activator receptor level of 2.83 ng/dL. No participant developed cardiomyopathy based on serial echocardiography by one-year follow-up. The median percent change in left ventricular strain was -4.3% at 6-month follow-up and absolute changes in cardiac biomarkers were clinically insignificant. There were no significant associations between soluble urokinase plasminogen activator receptor and these markers of cardiotoxicity (all p > 0.05).ConclusionsIn this breast cancer cohort, doxorubicin treatment was associated with a very low risk for cardiotoxicity. Across this narrow range of clinical endpoints, soluble urokinase plasminogen activator receptor was not associated with markers of subclinical cardiotoxicity. Further studies are needed to clarify the prognostic utility of soluble urokinase plasminogen activator receptor in doxorubicin-associated cardiomyopathy and should include a larger cohort of leukemia and lymphoma patients who receive higher doses of doxorubicin.

Effect of istradefylline on postural abnormalities in patients with Parkinson's disease: An association study of baseline postural angle measurements with changes in Unified Dystonia Rating Scale total score

In our previous study, istradefylline treatment in patients with Parkinson's disease (PD) improved postural abnormalities (PAs), as seen from a decrease in the mean Unified Dystonia Rating Scale (UDRS) total score from week 0 to week 24. A subgroup analysis based on baseline clinical characteristics investigated the association between improvement in the UDRS total score and istradefylline treatment. However, the association between an objective assessment of PAs and improvement in the UDRS total score is unclear. This ad hoc analysis investigated the association between improvement in the UDRS total score after istradefylline treatment and baseline trunk and neck angles, objective assessments of PAs, measured from patients' photographs taken in the previous study. The patients (n = 31) were stratified into groups based on the trunk forward flexion angle (TFFA), trunk lateral flexion angle (TLFA), and neck flexion angle (NFA) values at baseline. From week 0 to week 24, significant improvements in the UDRS total score were found in median percent change (−8.33% [interquartile range: −43.97, 0.00], P = 0.039) in patients with equal to or above the median TFFA values, and in median change (−‍1.50 [−9.25, 0.00], P = 0.015) and median percent change (−13.33% [−50.47, 0.00], P = 0.009) in patients with equal to or above the median TLFA values. Patients with more advanced PAs showed more consistent improvements in the UDRS total score with istradefylline. Baseline TFFA and TLFA values, which are objective values, may be useful to assess the istradefylline effectiveness in patients with PD and PAs.

Changes in Classified Precipitation in Iran

Changes in classified precipitation in Iran and its relationship with global mean surface temperature (GMST) have not been comprehensively investigated. Therefore, this study analyzed changes in precipitation of different intensities over Iran for the 1987–2017 period. Results show that the total annual precipitation (PRCPTOT) and the number of wet days (RR) have significantly decreased over Iran. Also, the mean precipitation intensity (SDII) has increased somewhat. There is a non-uniform change for three intensity categories of precipitation. The amounts (frequency) of light, moderate, and heavy precipitation have significantly decreased at 47% (57.9%), 18.7% (15.8%), and 3.94% (7.9%) of stations respectively. Therefore, the decrease in the amount and frequency of light and moderate precipitation is more severe than heavy precipitation and the proportion of heavy precipitation to the total annual precipitation has increased somewhat during 1987-2017. Overall, the result shows that the intensity of decreasing trends of amount and frequency of precipitation has increased from the south (east) to the north (west) of Iran. Also, SDII has increased from the south (east) to the north (west) of Iran. The sensitivity value was obtained by calculating the ratio of linear trends of precipitation indices and GMST. The regional median sensitivity and percentage change in PRCPTOT, RR, and SDII per 1-kelvin increase in GMST are -6.1%, -11.2%, and 12.9% respectively. Considering that Iran is located in the arid subtropical region, a significant decrease in the amount and frequency of precipitation may have destructive effects on water resources.

Adherence of denosumab treatment for low bone mineral density in Japanese people living with HIV: a retrospective observational study

BackgroundLong-term care issues, specifically metabolic bone disorders, are a concern for people living with human immunodeficiency virus (PLWH) who undergo life-long antiretroviral therapy (ART). Previous clinical trials with denosumab, an anti-RANKL antibody inhibitor, have revealed its effectiveness in increasing bone mineral density (BMD) in patients with osteoporosis. However, there are limited data on adherence and effectiveness of denosumab treatment for osteoporosis in PLWH. Hence, this study aimed to investigate the adherence and effectiveness of denosumab treatment for osteoporosis in Japanese PLWH.MethodsThis study is a retrospective exploratory analysis of 29 Japanese PLWH who initiated denosumab treatment for osteoporosis, between 2013 and 2021. The study included patients who received at least one dose of denosumab every 6 months. Adherence and persistence were defined as receiving two consecutive injections of denosumab 6 months ± 4 weeks apart and 6 months + 8 weeks apart, respectively. The primary outcome measure of the study was the adherence of denosumab treatment for 24 months. The secondary outcome measures included treatment persistence and BMD. The period after January 2020 was defined as the coronavirus disease 2019 (COVID-19) pandemic period, and its impact on adherence was investigated.ResultsThe treatment adherence rates at 12 and 24 months were 89.7% and 60.7%, respectively. By contrast, the treatment persistence at 12 and 24 months was 100% and 85.7%, respectively. More patients in the group who initiated denosumab treatment after the COVID-19 pandemic reached non-adherence than in the group who initiated denosumab treatment before the pandemic. BMD at the lumbar spine and femoral neck significantly increased compared to that at baseline, with median percentage changes of 8.7% (p < 0.001) and 3.5% (p = 0.001), respectively.ConclusionsThe results showed that patients in the study had a high rate of non-adherence but a lower rate of non-persistence. Additionally, PLWH on ongoing ART experienced increased BMD with denosumab treatment. This study provides an opportunity to improve future strategies for denosumab treatment in the Japanese PLWH.

HCG trends after mifepristone and misoprostol for undesired pregnancy of unknown location

ObjectivesTo describe human chorionic gonadotropin (hCG) trends for patients with a pregnancy of unknown location (PUL) presenting for medication abortion by management strategy and outcome. Study designThis retrospective cohort study included patients presenting for medication abortion with a PUL at ≤42 days gestation managed with either (1) immediate mifepristone with serial hCG follow-up (same-day-start) or (2) hCG testing every 48 to 72 hours ± ultrasonography to confirm pregnancy location followed by treatment (delay-for-diagnosis). The primary outcome was percent hCG change over time between presentation and diagnosis, summarized using a multivariate regression model. ResultsOf the 55 same-day-start patients, none were treated for ectopic. The eight who eventually required suction curettage had median hCG percent changes (interquartile range) on days 3, 4, and 5 of +57% (−14 to 127; n = 2), +292% (226–353; n = 4), and +392% (n = 1), while the 41 successful medication abortions had declines of −64% (n = 1), −65% (−75 to −27; n = 17), and −77% (−85 to −68; n = 13). Of the 380 delay-for-diagnosis patients, the 30 ectopic pregnancies had day 3, 4, and 5 changes of +38% (−17 to 56; n = 14), +50% (17–71; n = 7), and +115% (87–177; n = 4). None of the ectopic pregnancies declined ≥50% by days 3 to 5. The hCG trend for ectopic pregnancies differed from successful medication abortions (p < 0.01), but not medication abortions with retained intrauterine pregnancies (p = 0.41). ConclusionsSerum hCG trends can help differentiate ectopic pregnancy from successful medication abortion, but cannot distinguish between ectopic and retained intrauterine pregnancy. ImplicationsSerial serum hCG testing is effective for confirming successful medication abortion and identifying patients requiring further follow-up among patients undergoing medication abortion for an undesired PUL.

Alternative metrics for characterizing longer-term clinical outcomes in difficult-to-treat depression: II. Sensitivity to treatment effects.

Characteristics of difficult-to-treat depression (DTD), including infrequent symptom remission and poor durability of benefit, compel reconsideration of the outcome metrics historically used to gauge the effectiveness of antidepressant interventions. Self-report and clinician assessments of depression symptom severity were obtained regularly over a 2-year period in a difficult-to-treat depression registry sample receiving treatment as usual (TAU), with or without vagus nerve stimulation (VNS). Alternative outcome metrics for characterizing symptom change were compared in effect size and discriminating power in distinguishing the vagus nerve stimulation + treatment as usual and treatment as usual treatment groups. We expected metrics based on remission status to produce weaker between-group separation than those based on the classifications of partial response or response and metrics that integrate information over time to produce greater separation than those based on single endpoint assessment. Metrics based on remission status had smaller effect size and poorer discrimination in separating the treatment groups than metrics based on partial response or response classifications. Metrics that integrated information over the 2-year observation period had stronger performance characteristics than those based on symptom scores at single endpoint assessment. For both the clinician-rated and self-report depression ratings, the metrics with the strongest performance characteristics were the median percentage change in symptom scores over the observation period and the proportion of the observation period in partial response or better. In difficult-to-treat depression, integrative symptom severity-based and time-based measures are sensitive and informative outcomes for assessing between-group treatment effects, while metrics based on remission status are not.

Efficacy and Safety of XEN1101, a Novel Potassium Channel Opener, in Adults With Focal Epilepsy

Many patients with focal epilepsy experience seizures despite treatment with currently available antiseizure medications (ASMs) and may benefit from novel therapeutics. To evaluate the efficacy and safety of XEN1101, a novel small-molecule selective Kv7.2/Kv7.3 potassium channel opener, in the treatment of focal-onset seizures (FOSs). This phase 2b, randomized, double-blind, placebo-controlled, parallel-group, dose-ranging adjunctive trial investigated XEN1101 over an 8-week treatment period from January 30, 2019, to September 2, 2021, and included a 6-week safety follow-up. Adults experiencing 4 or more monthly FOSs while receiving stable treatment (1-3 ASMs) were enrolled at 97 sites in North America and Europe. Patients were randomized 2:1:1:2 to receive XEN1101, 25, 20, or 10 mg, or placebo with food once daily for 8 weeks. Dosage titration was not used. On completion of the double-blind phase, patients were offered the option of entering an open-label extension (OLE). Patients not participating in the OLE had follow-up safety visits (1 and 6 weeks after the final dose). The primary efficacy end point was the median percent change from baseline in monthly FOS frequency. Treatment-emergent adverse events (TEAEs) were recorded and comprehensive laboratory assessments were made. Modified intention-to-treat analysis was conducted. A total of 325 patients who were randomized and treated were included in the safety analysis; 285 completed the 8-week double-blind phase. In the 325 patients included, mean (SD) age was 40.8 (13.3) years, 168 (51.7%) were female, and 298 (91.7%) identified their race as White. Treatment with XEN1101 was associated with seizure reduction in a robust dose-response manner. The median (IQR) percent reduction from baseline in monthly FOS frequency was 52.8% (P < .001 vs placebo; IQR, -80.4% to -16.9%) for 25 mg, 46.4% (P < .001 vs placebo; IQR, -76.7% to -14.0%) for 20 mg, and 33.2% (P = .04 vs placebo; IQR, -61.8% to 0.0%) for 10 mg, compared with 18.2% (IQR, -37.3% to 7.0%) for placebo. XEN1101 was generally well tolerated and TEAEs were similar to those of commonly prescribed ASMs, and no TEAEs leading to death were reported. The efficacy and safety findings of this clinical trial support the further clinical development of XEN1101 for the treatment of FOSs. ClinicalTrials.gov Identifier: NCT03796962.

Effect of multiple loading FIT sample collection devices on faecal haemoglobin concentration.

Faecal immunochemical tests (FIT) are routinely used in colorectal cancer (CRC) screening programmes around the world. More recently, quantitative FIT has been recommended to help triage patients presenting to primary care with symptoms suggestive of CRC. Participants collect faecal samples using sampling probes which are inserted into sample collection devices (SCDs) containing preservative buffer. The SCDs have an internal collar designed to remove excess sample. The aim of this study was to investigate the impact of multiple loading on faecal haemoglobin concentration (f-Hb) using SCDs of four FIT systems. Pools of f-Hb negative samples were spiked with blood, homogenised and loaded into SCDs 1, 3 and 5 times, with insertion of the sampling probes into the SCDs with and without mixing between loads. The f-Hb was measured using the relevant FIT system. The percentage change in f-Hb for multiple loads was compared with a single load for each system for the mixed and unmixed groups. The p values show a significant difference (p < 0.05) in the mass and f-Hb for the mixed and unmixed group, for 1-3 and 1-5 loads for all systems. The median percentage change in f-Hb for the mixed is higher than the unmixed group. This study showed that multiple loading does significantly increase the f-Hb in the SCDs.

Comparison of anterior cruciate ligament reconstruction with and without concomitant meniscal repair: A prospective comparative study

Background: The treatment of anterior cruciate ligament (ACL) injury includes ACL reconstruction (ACL-R) or ligament preservation, where the former is considered the gold standard. But in meniscal injury, though commonly followed is menisectomy, meniscal repair has gained popularity and success which necessitates the analysis of outcome between ACL-R + meniscal repair and ACL-R + menisectomy as clear consensus have not been established so far in deciding the better overall procedure with respect to function. Methods: This is a prospective, comparative study done in 122 patients with ACL injury and medial/ lateral meniscus in south Indian population at a single center. Where meniscal repair (61) and menisectomy (partial/complete, n=61) with ACL-R were carried out and were evaluated pre-operatively, during the postoperative period at 6 weeks, 3 months, and 6 months of follow-up for function and compared. The primary outcome evaluated was pain and other symptoms like limping, giving way, swelling and locking were also noted and analysed using KOOS, IKDC and Lysholm scores. Results: The mean difference in KOOS score in postoperative period, at 3 and 6months were significantly higher among the ACL-R + meniscal repair group than the ACL-R + meniscectomy group which is statistically significant. Moreover the median percentage change in IKDC and Lysholm scores from baseline to postoperative 3 and 6 months were significantly higher in ACL-R + meniscal repair group than the other. Conclusion: The meniscal repair with ACL-R has a lower failure rate and shows better functional outcomes than the other group which underwent ACL-R and meniscectomy. Keywords: anterior cruciate ligament reconstruction; ACL-R; meniscectomy; meniscal repair; meniscal tear

Changes in physical function in older women with endometrial cancer with or without adjuvant therapy.

To evaluate changes in physical function (PF) for older women with endometrial cancer (EC) + / - adjuvant therapy in the Women's Health Initiative Life and Longevity after Cancer cohort. This study examined women ≥ 70years of age with EC with available treatment records. Change in PF was measured using the RAND-36 and compared between groups using Wilcoxon rank-sum tests. Multivariable median regression was used to compare the changes in scores while adjusting for confounding variables. Included in the study were 287 women, 150 (52.3%) women who did not receive adjuvant therapy and 137 (47.7%) who received adjuvant therapy. When comparing PF scores, there was a statistically significant difference in the median percent change in functional decline, with a greater decline in those who received adjuvant therapy (- 5.9% [- 23.5 to 0%]) compared to those who did not (0 [- 18.8 to + 6.7%]), p = 0.02). Results were not statistically significant after multivariable adjustment, but women who underwent chemotherapy had a greater percent change (median ∆ - 13.8% [- 35.5 to 0%]) compared to those who received radiation alone (median ∆ - 5.9% [- 31.3 to 0%]) or chemotherapy and radiation (median ∆ - 6.5% [- 25.8 to + 5.7%]. Older women with EC who received adjuvant therapy experienced greater change in PF than those who did not receive adjuvant therapy, particularly women who received chemotherapy. These results were not statistically significant on multivariate analysis. EC survivors may experience changes in PF because of chemotherapy and/or radiation therapy. Additional supportive care may need to be provided to older women to mitigate functional decline.

564 Pelvic Fracture Incidence in EU15+ Countries: Trends Over a 30-Year Period

Abstract Aim Pelvic fractures (PF) are relatively uncommon but significant injuries accounting for approximately 3% of all skeletal injuries. We aimed to assess the burden of PFs across high health expenditure countries by describing the trends in PF incidence rates over the last three decades. Method Using the Global Burden of Disease (GBD) Study database, we extracted sex specific PF age-standardised incidence rates (ASIRs) from 1990-2019 for each of the 19 European Union (EU) 15+ countries. We performed Joinpoint regression analysis to further characterise the trends. Results Over the 30-year period of study, 89% of countries experienced a decline in ASIRs for males, with a median percentage change of -11.8%, in comparison to females where 53% of countries experienced an increase in ASIR (median percentage increase of +3.1%). For females, the largest increases in PF incidence were observed in the Netherlands and Belgium; these were also the only two counties with increased overall PF incidence in males over the study period observed. The countries with the greatest decrease in ASIRs were Italy and Denmark for females and Portugal and Spain for males. Joinpoint regression identified that over the time periods covered by the most recent trends, PF incidence rates had increased in 58% of countries for females and 52% of countries for males. Conclusions We found overall decreased incidences of PFs amongst males over the last 3 decades, compared with increased incidence in females. However, joinpoint regression analysis demonstrated a trend towards rising incidence of PFs amongst both males and females in recent years.

Safety, tolerability, and efficacy of adjunctive lacosamide in pediatric patients with epilepsy syndromes associated with generalized seizures: Phase 2, open-label exploratory trial.

To evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of lacosamide (up to 12 mg/kg/day or 600 mg/day) as adjunctive therapy in pediatric patients with epilepsy syndromes associated with generalized seizures. Phase 2, multicenter, open-label exploratory trial (SP0966; NCT01969851; 2012-001446-18) of oral lacosamide for epilepsy syndromes associated with generalized seizures in pediatric patients ≥1 month to <18 years of age taking one to three concomitant antiseizure medications. The trial comprised a 6-week prospective baseline period, 6-week flexible titration period, and 12-week maintenance period. 55 patients (mean age: 9.2 years; 56.4% male) took at least one dose of lacosamide and had at least one post-baseline efficacy-related assessment. The median treatment duration was 127.0 days. There were no clinically significant mean or median changes or worsening from baseline to end of the titration period in the count of generalized spike-wave discharges per interpretable hour on 24-hour ambulatory electroencephalogram recordings, or from baseline to the maintenance period in mean and median days with any generalized or focal to bilateral tonic-clonic seizures per 28 days. Treatment-emergent adverse events (TEAEs) were reported by 49 (89.1%) patients, and three (5.5%) patients discontinued due to TEAEs. The median change and median percentage change in days with any generalized or focal to bilateral tonic-clonic seizures per 28 days from baseline to the maintenance period were both 0. Trends towards improvement (decrease) were observed in median change and median percentage change in days with each individual seizure type (absence, myoclonic, clonic, tonic, tonic-clonic, atonic, and focal to bilateral tonic-clonic) per 28 days. Safety findings were consistent with the known safety profile of lacosamide and were as expected for the pediatric population. There was no worsening of generalized seizures with lacosamide. Limitations include the inability to correlate spike and wave data with clinical outcomes, and lack of similar studies against which the results can be compared.

Long-Term Efficacy and Safety Among Patients With Severe Eosinophilic Asthma Treated With Mepolizumab and Its Effect on Small Airways

The major problem at the Cleveland Allergy and Asthma Center was the need for additional therapy for severe eosinophilic asthma patients who were steroid-dependent or required frequent bursts of prednisone. The objectives of this study were to determine the efficacy of monthly mepolizumab (MP) injections up to 6½ years using Asthma Control Quesitonnaire-7 (ACQ-7), forced expiratory volume in 1 second (FEV1), forced expiratory flow at 25% to 75% (FEF25%-75%) overall and among super-responders, and to understand whether FEF25%-75% is an effective parameter to evaluate MP efficacy. We reviewed the charts of 67 patients with severe eosinophilic asthma and compared the results between 47 super-responders and the rest of the cohort regarding ACQ-6, ACQ-7, eosinophils, FEV1, and FEF25%-75%. The groups of super-responders and all other patients were described with respect to initial and current values of the study end points using medians and 25th and 75th percentiles. Changes from the initial to the current values in the study end points were measured using percent changes. The Wilcoxon signed rank test was used within each group to test the null hypothesis of 0 median percent change. After 6½ years, there were no significant changes in FEV1. The FEF25%-75%, had a significant median percent increase of 40% among the super-responders (P < .001), which was substantially higher (P= .026) than the medianpercent increase of 13.8% observed among all other patients. The use of MP up to 6½ years was safe and effective, with significant changes to ACQ-7 and FEF25%-75% associated with MP treatment, but not the FEV1. A higher magnitude of changes was observed among super-responders than the rest of the cohort. Changes in FEF25%-75% were more meaningful than changes in FEV1 in evaluating pulmonary function responsiveness of severe eosinophilic asthma to MP.

The Efficacy and Safety of Surufatinib Combined with Anti PD-1 Antibody Toripalimab in Neoadjuvant Treatment of Locally Advanced Differentiated Thyroid Cancer: A Phase II Study.

Surgery is the primary treatment for locally advanced differentiated thyroid cancer (DTC). However, some locally advanced patients are not candidates for R0/1 resection. There is limited evidence of neoadjuvant treatment in locally advanced DTC. Surufatinib targets multiple kinases, which is efficient, tolerable, and safe in patients with radioiodine-refractory DTC. In addition, surufatinib plus toripalimab (an anti-PD-1 antibody) showed encouraging antitumor activity in advanced solid tumors. This study was designed to evaluate the efficacy and safety of surufatinib plus toripalimab in locally advanced DTC in the neoadjuvant setting. In this single-arm, phase II study, patients with pathologically confirmed unresectable or borderline resectable DTC were eligible and received a combination of 250mg of surufatinib (orally daily) with 240mg of toripalimab (intravenous, every 3weeks). Treatment continued until satisfied for curative surgery, disease progression, withdrawal of consent, unacceptable toxicity, or investigator decision. Primary endpoint was objective response rate (ORR). Secondary endpoints included R0/1 resection rate, adverse events (AEs), etc. RESULTS: Ten patients were enrolled and received at least 4 cycles of treatment. The ORR was 60%. Nine patients received R0/1 resections after neoadjuvant treatment. The median best percentage change in the sum of the target lesion diameter was 32%. Most adverse events (AEs) were grade 1 or 2. Surufatinib in combination with toripalimab as neoadjuvant therapy for locally advanced DTC was feasible, and the majority of patients achieved R0/1 resection. It represents a new option for locally advanced DTC and needs further investigation.

Serial Nigrostriatal Dopaminergic Imaging in Mild Cognitive Impairment With Lewy Bodies, Alzheimer Disease, and Age-Matched Controls.

Progressive nigrostriatal pathway degeneration occurs in individuals with dementia with Lewy bodies (LB). Our objective was to investigate whether repeat 123[I]-N-(3-fluoropropyl)-2β-carboxymethoxy-3β-(4-iodophenyl) nortropane (FP-CIT) single photon emission computed tomography (SPECT) can identify progressive dopaminergic loss in mild cognitive impairment (MCI) with Lewy bodies (MCI-LB). Individuals with MCI-LB and MCI due to Alzheimer disease (MCI-AD) underwent comprehensive clinical assessment, 123[I]-FP-CIT SPECT at baseline and annual reviews, and baseline cardiac 123 iodine metaiodobenzylguanidine (I-MIBG). Mixed-effects models were used to investigate changes in 123[I]-FP-CIT specific binding ratio (SBR) in the striatum for each diagnostic group compared with controls. The time interval to the development of a quantitatively abnormal 123[I]-FP-CIT SPECT in the possible and probable MCI-LB groups was determined as the time it took for these groups to reach a striatal uptake 2 SDs below aged-matched controls. Test-retest variation was assessed using baseline and repeat scans in controls. We recruited 20 individuals with MCI-AD, 11 with possible MCI-LB, 25 with probable MCI-LB, and 29 age-matched controls. The mean time between baseline and the final image was 1.6 years (SD = 0.9, range 1.0-4.3). The annual estimated change in SBR was 0.23 for controls (95% CI -0.07 to 0.53), -0.09 (-0.55 to 0.36) for MCI-AD, -0.50 (-1.03 to 0.04) for possible MCI-LB, and -0.48 (-0.89 to -0.06) for probable MCI-LB. The median annual percentage change in SBR in MCI-LB was -5.6% (95% CI -8.2% to -2.9%) and 2.1% (-3.5% to 8.0%) for MCI-AD. The extrapolated time for a normal scan to become abnormal was 6 years. Controls and MCI-AD showed no significant change in dopaminergic binding over time. The mean test-retest variation in controls was 12% (SD 5.5%), which cautions against overinterpretation of small changes on repeat scanning. Progressive dopaminergic loss in the striatum is detectable using 123[I]-FP-CIT SPECT in MCI-LB at a group level. In clinical practice, individual change in striatal 123[I]-FP-CIT uptake seems to be of limited diagnostic value because of high test-retest variation. This study provides Class II evidence that longitudinal declines in striatal uptake measured using 123[I]-FP-CIT SPECT are associated with MCI due to Lewy body disease but not MCI due to Alzheimer disease.

The use of novel diffuse optical spectroscopies for improved neuromonitoring during neonatal cardiac surgery requiring antegrade cerebral perfusion.

Surgical procedures involving the aortic arch present unique challenges to maintaining cerebral perfusion, and optimal neuroprotective strategies to prevent neurological injury during such high-risk procedures are not completely understood. The use of antegrade cerebral perfusion (ACP) has gained favor as a neuroprotective strategy over deep hypothermic circulatory arrest (DHCA) due to the ability to selectively perfuse the brain. Despite this theoretical advantage over DHCA, there has not been conclusive evidence that ACP is superior to DHCA. One potential reason for this is the incomplete understanding of ideal ACP flow rates to prevent both ischemia from underflowing and hyperemia and cerebral edema from overflowing. Critically, there are no continuous, noninvasive measurements of cerebral blood flow (CBF) and cerebral oxygenation (StO2) to guide ACP flow rates and help develop standard clinical practices. The purpose of this study is to demonstrate the feasibility of using noninvasive, diffuse optical spectroscopy measurements of CBF and cerebral oxygenation during the conduct of ACP in human neonates undergoing the Norwood procedure. Four neonates prenatally diagnosed with hypoplastic left heart syndrome (HLHS) or a similar variant underwent the Norwood procedure with continuous intraoperative monitoring of CBF and cerebral oxygen saturation (StO2) using two non-invasive optical techniques, namely diffuse correlation spectroscopy (DCS) and frequency-domain diffuse optical spectroscopy (FD-DOS). Changes in CBF and StO2 due to ACP were calculated by comparing these parameters during a stable 5 min period of ACP to the last 5 min of full-body CPB immediately prior to ACP initiation. Flow rates for ACP were left to the discretion of the surgeon and ranged from 30 to 50 ml/kg/min, and all subjects were cooled to 18°C prior to initiation of ACP. During ACP, the continuous optical monitoring demonstrated a median (IQR) percent change in CBF of -43.4% (38.6) and a median (IQR) absolute change in StO2 of -3.6% (12.3) compared to a baseline period during full-body cardiopulmonary bypass (CPB). The four subjects demonstrated varying responses in StO2 due to ACP. ACP flow rates of 30 and 40 ml/kg/min (n = 3) were associated with decreased CBF during ACP compared to full-body CPB. Conversely, one subject with a higher flow6Di rate of 50 ml/kg/min demonstrated increased CBF and StO2 during ACP. This feasibility study demonstrates that novel diffuse optical technologies can be utilized for improved neuromonitoring in neonates undergoing cardiac surgery where ACP is utilized. Future studies are needed to correlate these findings with neurological outcomes to inform best practices during ACP in these high-risk neonates.

Use of Ambroxol as Therapy for Gaucher Disease

Ambroxol was identified as an enhancer of stability and residual activity of several misfolded glucocerebrosidase variants in 2009. To assess hematologic and visceral outcomes, biomarker changes, and safety of ambroxol therapy for patients with Gaucher disease (GD) without disease-specific treatment. Patients with GD who could not afford enzyme replacement therapy were enrolled and received oral ambroxol from May 6, 2015, to November 9, 2022, at Xinhua Hospital, affiliated with Shanghai Jiao Tong University School of Medicine, Shanghai, China. Thirty-two patients with GD (29 with GD type 1, 2 with GD type 3, and 1 with GD intermediate types 2-3) were enrolled. Of those, 28 patients were followed up for longer than 6 months; 4 were excluded due to loss of follow-up. Data analyses were performed from May 2015 to November 2022. An escalating dose of oral ambroxol (mean [SD] dose, 12.7 [3.9] mg/kg/d). Patients with GD receiving ambroxol were followed up in a genetic metabolism center. Biomarkers of chitotriosidase activity and glucosylsphingosine level, liver and spleen volumes, and hematologic parameters were measured at baseline and various time points throughout the ambroxol treatment. A total of 28 patients (mean [SD] age, 16.9 [15.3] years; 15 male patients [53.6%]) received ambroxol for a mean (SD) duration of 2.6 (1.7) years. Two patients with severe symptoms at baseline experienced deterioration of hematologic parameters and biomarkers and were deemed nonresponders; clinical response was observed in the other 26 patients. After 2.6 years of ambroxol treatment, the mean (SD) hemoglobin concentration improved from 10.4 (1.7) to 11.9 (1.7) g/dL (mean [SD], 1.6 [1.7] g/dL; 95% CI, 0.8-2.3 g/dL; P < .001), and the mean (SD) platelet count improved from 69 (25) to 78 (30) × 103/µL (mean [SD], 9 [22] × 103/µL; 95% CI, -2 to 19 × 103/µL; P = .09). The mean (SD) spleen volume decreased from 17.47 (7.18) to 12.31 (4.71) multiples of normal (MN) (mean [SD], -5.16 [5.44] MN; 95% CI, -10.19 to -0.13; P = .04), and the mean (SD) liver volume decreased from 1.90 (0.44) to 1.50 (0.53) MN (mean [SD], -0.39 [0.42] MN; 95% CI, -0.75 to -0.04; P = .03). Biomarker median percentage changes from baseline were -43.1% for chitotriosidase activity (from 14 598 [range, 3849-29 628] to 8312 [range, 1831-16 842] nmol/mL/h; z = -3.413; P = .001) and -34.1% for glucosylsphingosine level (from 251.3 [range, 73.6-944.2] to 165.7 [range, 21.3-764.8] ng/mL; z = -2.756; P = .006). Patients were divided into subgroups according to age when initiating treatment; those who received treatment at a younger age (mean [SD] age, 6.3 [2.7] years) experienced more rapid improvements: hemoglobin concentration increased by 16.5% (from 10.3 [1.5] to 12.0 [1.5] g/dL; mean [SD] change, 1.6 [1.6] g/dL; 95% CI, 0.7-2.5 g/dL; P = .002), and platelet count increased by 12.0% (from 75 [24] to 84 [33] × 103/µL; mean [SD] change, 9 [26] × 103/µL; 95% CI, -5 to 24 × 103/µL; P = .17); whereas chitotriosidase activity decreased by 64.0% (from 15 710 [range, 4092-28 422] to 5658 [range, 1146-16 843] nmol/mL/h; z = -2.803; P = .005), and glucosylsphingosine level decreased by 47.3% (from 248.5 [range, 122.8-674.9] to 131.0 [range, 41.1-448.5] ng/mL; z = -2.385; P = .02). Three of the 28 patients experienced mild and transient adverse events. In this case series of ambroxol repurposing among patients with GD, long-term treatment with ambroxol was safe and associated with patient improvement. Improvements in hematologic parameters, visceral volumes, and plasma biomarkers were larger among patients with relatively mild symptoms of GD and patients who received initial treatment at younger ages.

Computed tomographic features of double aortic arch in six dogs.

Double aortic arch (DAA) is a rare, congenital anomaly in small animals, resulting in a complete vascular ring encircling the esophagus and trachea, and subsequent compression of these organs. Few studies have reported utilizing CT angiography (CTA) for diagnosing DAA in dogs; thus, the imaging features are currently lacking in the literature. The objectives of this retrospective, multicenter, descriptive case series were to report the clinical and CTA characteristics of DAA in surgically treated cases. Medical records and CTA images were reviewed. Six juvenile dogs met the inclusion criteria (median age: 4.2 months; range: 2-5 months). The most common clinical signs included chronic regurgitation (100%), decreased body condition (67%), and coughing (50%). Common CTA features of DAA included a dominant left aortic arch (median diameter: 8.1mm) and minor right aortic arch (median diameter: 4.3mm; 83%), an aberrant right subclavian artery arising directly from the right aortic arch (83%), segmental esophageal constriction (100%), and variable degrees of dilation cranial to the heart base, and marked tracheal luminal compression (median percent change: -55%; 100%) and leftward curvature of the trachea at the level of the bifurcation of the aortic arches (100%). All dogs underwent successful surgical correction with only minor postoperative complications. Due to the similarity of clinical and imaging characteristics described to that of other forms of vascular ring anomalies (VRA), CTA is vital for the specific diagnosis of DAA in dogs.

Open-label study to investigate the safety and efficacy of adjunctive perampanel in pediatric patients (aged 4 to

PurposeTo evaluate the safety and tolerability of adjunctive perampanel in a Japanese subpopulation of Study 311 (NCT02849626), which was a global, multicenter, open-label, single-arm study of children (aged 4 to <12 years) with inadequately controlled focal-onset seizures (FOS), with or without focal to bilateral tonic-clonic seizures (FBTCS) or generalized tonic-clonic seizures (GTCS). MethodsStudy 311 comprised a Core Study, Extension A, and Extension B; this report focuses on the Japanese patient subgroup in the Core Study only. In the Core Study, Japanese patients (FOS only) received adjunctive perampanel ≤12 mg/day in a 23-week Treatment Phase. Endpoints included safety/tolerability (primary) and median percent change in seizure frequency per 28 days from baseline. Patients were stratified by age and concomitant enzyme-inducing anti-seizure medication (EIASM) use. ResultsOf 65 enrolled Japanese patients, 56 completed the Core Study and nine withdrew. The most common reason for discontinuation was adverse events (AEs) (n = 4 [6.2%]). The mean (standard deviation) daily dose of perampanel in Japanese FOS patients was 5.8 (2.2) mg/day. During the Core Study, treatment-emergent AEs (TEAEs) were reported by 89% of Japanese patients, most commonly nasopharyngitis (28%) and somnolence (28%). The median percent reduction in seizure frequency per 28 days from baseline was 37% and the lower limit of the 95% CI was greater than 10.5%, satisfying the pre-defined efficacy criteria. Perampanel was effective regardless of age or concomitant EIASM use. ConclusionPerampanel as adjunctive therapy is generally safe, well-tolerated, and efficacious in Japanese children aged 4 to <12 years with FOS (with/without FBTCS).