2-day Intervals Research Articles

Abstract 3481: Pharmacokinetics of alofanib and biomarker analysis in patients with advanced gastric cancer: A phase 1b study

Abstract Alofanib is a potent, small molecule, allosteric inhibitor that binds to the non-active extracellular site of IIIc and IIIb FGFR2 isoforms. Phase 1b clinical study (RPT835GC1B) met its primary endpoints and recommended phase 2 dose was described early. Here, we present pharmacokinetics (PK) and results of biomarker analysis. Alofanib was administered daily intravenously for 5-days followed by a 2-day interval (rest). There were five dose levels using a 3 + 3 design. 21 patients have been enrolled in the study. Patients were Caucasian (100%), predominantly male (71%), 67% had 2 and more metastatic sites, including liver (43%) and bone (14.3%) metastases, 19% had ECOG PS 2, and were heavily pretreated (86% had previous 3 and more lines of therapy). The PK and biomarker analysis set included 18 patients. FGFR2 amplification was accessed by FISH with ZytoLight SPEC FGFR2/CEN 10 Dual Color Probe and FGFR2 expression was accessed by IHC with antibody 1G3 (Abcam (ab 5820). Table summarizes PK data. The geometric mean values of Cmax, AUC0-t, T1/2, Vd increased and CL, Kel decreased approximately dose-proportionally after single dosing, similar to previous preclinical studies. The decrease in the mean value of the Vd for a dose of 350 mg/m2 may be associated with a significant increase in AUC0-t. No correlations between PK values and objective response rate (n=2; 9.5%), progression-free (median 3.63 months (95% CI, 1.58 - 5.68) and overall (median 7.0 months (3.82 - 10.18) survival as well as in patients with liver metastases were found (all P>0.1). A positive FGFR2 IHC expression was observed in all tumor cells and a weak positive reaction in normal epithelium. FGFR2 amplification was confirmed by FISH in 1 (5.6%) patient.Alofanib PK in a gastric patient population is well characterized, supporting the use of a once-daily 350 mg/m2 dose. In further studies, the evaluation of FGFR2 amplification seems to be important. Cohort 1 Cohort 2 Cohort 3 Cohort 4 Cohort 5 50 mg/m2 100 mg/m2 165 mg/m2 250 mg/m2 350 mg/m2 Cmax, mcg/ml (CV%) 21.4 (32.3) 23.7 (18.4) 44.7 (15.5) 72.8 (64.3) 145.9 (42.7) AUC0-t, mcg*h/ml (CV%) 2.3 (31.9) 6.6 (14.2) 13.3 (49.9) 23.8 (8.7) 74.0 (57.5) Vd, ml/m2 (CV%) 4006.1 (28.3) 4907.5 (14.7) 5676.8 (26.6) 6686.7 (11) 3823.0 (63.8) CL, ml/h/m2 (SD) 19609.5 (7740) 14028.2 (1990) 11910.5 (8740) 10011.0 (827) 4183.0 (2420) Kel, 1/h (CV%) 4.9 (15.3) 2.9 (2.8) 2.1 (41.2) 1.5 (3.8) 1.1 (47.0) T1/2, h (SD) 0.1 (0.024) 0.2 (0.01) 0.3 (0.118) 0.5 (0.0171) 0.6 (0.293) Citation Format: Grigory Raskin, Vasily Kazey, Svetlana Gorbacheva, Aiyyna Nikiforova, Galina Statsenko, Elena Artamonova, Liubov Vladimirova, Natalia Besova, Anastasia Mochalova, Ivan Rykov, Vladimir Moiseyenko, Igor Utyashev, Sergei Iugai, Nadezhda Dragun, Dmitry Reznikov, Evgenia Gavrilova, Sergei Tjulandin, Ilya Tsimafeyeu. Pharmacokinetics of alofanib and biomarker analysis in patients with advanced gastric cancer: A phase 1b study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3481.

SEX DIFFERENCES IN AMBULATORY BLOOD PRESSURE TRAJECTORIES AND BLOOD PRESSURE VARIABILITY IN HEMODIALYSIS PATIENTS

Objective: Ambulatory blood pressure (BP) control is worse in men than in women with chronic kidney disease (CKD) and this may partially explain the faster CKD progression in men. The aim of this study is to investigate possible sex-differences in ambulatory BP levels, BP trajectories, and BP variability (BPV) in hemodialysis patients. Design and method: 129 male and 91 female hemodialysis patients that underwent 48-h ABPM with Mobil-O-Graph-NG were included in this analysis. Ambulatory BP levels over the 2-day interdialytic interval (including two daytime and two nighttime periods) were recorded. We calculated the standard deviation (SD), weighted SD (wSD), coefficient of variation (CV), and average real variability (ARV) of BP with validated formulas. Results: Age, dialysis vintage, antihypertensive treatment and history of major comorbidities did not differ between men and women. Pre-dialysis SBP levels did not differ between men and women (145.1 ± 22.7 vs 145.9 ± 25.7mmHg, p = 0.808), but DBP was marginally higher in men (87.6 ± 14.0 vs 84.0 ± 13.7mmHg, p = 0.055). 48-h SBP/DBP (137.2 ± 17.4/81.9 ± 12.1mmHg vs 132.2 ± 19.2/75.9 ± 11.7mmHg, p = 0.045/ < 0.001) as well as DBP during the 1st and SBP/DBP during the 2nd 24-h period were significantly higher in men than in women. Similarly, daytime SBP/DBP was significantly higher in men (138.3 ± 17.5/83.2 ± 12.3mmHg vs 131.9 ± 19.4/76.4 ± 11.5mmHg. p = 0.011/< 0.001). No significant between-group differences were detected for nighttime SBP. All SBP variability indices were similar between men and women; DBP-SD, DBP-wSD and DBP-ARV were higher in men (44-h DBP-ARV 9.4 ± 1.8 vs 8.6 ± 1.9, p = 0.002). No significant differences were revealed in the dipping pattern between men and women. Conclusions: Ambulatory BP levels and trajectories, as well as DBP variability indices are higher in men than women hemodialysis patients. This worse ambulatory BP profile in male compared to female patients may impact on the incidence of cardiovascular events.

Long-term survival of Icelandic women following acute myocardial infarction

Objective. To evaluate the impact of sex on treatment and survival after acute myocardial infarction (AMI) in Iceland. Methods. A retrospective, nationwide cohort study of patients with STEMI (2008–2018) and NSTEMI (2013–2018) and obstructive coronary artery disease. Patient and procedural information were obtained from a registry and electronic health records. Survival was estimated with Kaplan–Meier method and Cox regression analysis used to identify risk factors for long-term mortality. Excess mortality from the AMI episode was estimated by comparing the survival with age- and sex-matched population in Iceland at 30-day interval. Results. A total of 1345 STEMI-patients (24% women) and 1249 NSTEMI-patients (24% women) were evaluated. Women with STEMI (mean age: 71 ± 11 vs. 67 ± 12) and NSTEMI (mean age: 69 ± 13 vs. 62 ± 12) were older and less likely to have previous cardiovascular disease. There was neither sex difference in the extent of coronary artery disease nor treatment. Although crude one-year post-STEMI survival was lower for women (88.7% vs. 93.4%, p = .006), female sex was not an independent risk factor after adjusting for age and co-morbidities after STEMI and was protective for NSTEMI (HR 0.67, 95% CI: 0.46–0.97). There was excess 30-day mortality in both STEMI and NSTEMI for women compared with sex-, age- and inclusion year-matched Icelandic population, but thereafter the mortality rate was similar. Conclusion. Women and men with AMI in Iceland receive comparable treatment including revascularization and long-term survival appears similar. Prognosis after NSTEMI is better in women, whereas higher early mortality after STEMI may be caused by delays in presentation and diagnosis.

Reliability of a Timeline Followback measure of caffeinated coffee consumption

Background and aimsThe Timeline Followback (TLFB) was initially developed to collect retrospective self- reports of alcohol and drug use. Since its development, several peer-reviewed papers have supported it as a sound psychometric measure for substance use and for several other behaviors. Worldwide, coffee is one of the most widely consumed beverages. Although early epidemiological research suggested that drinking coffee is associated with some health problems, several recent studies have found moderate coffee consumption to have an inverse association with mortality. Because of its widespread use, a psychometrically sound measure of coffee consumption would help better inform research and public health policies. DesignThis study investigated the test–retest reliability of a version of the TLFB modified to assess coffee consumption. Setting and participants98 clinical psychology doctoral students completed a 30-day coffee TLFB on two occasions separated by 14 days. MeasurementsParticipants used a computerized Survey Monkey™ version of the coffee TLFB to report their caffeinated coffee consumption for the same 30-day interval. For the first administration participants reported their consumption for the preceding 30 days, and for the second administration they reported on the preceding 45 days which included the earlier reporting interval. FindingsReliability coefficients were found to be very high (0.90–0.97). ConclusionsAs with other substance use versions of the TLFB, these results suggest the TLFB is a good method for measuring coffee consumption in research studies and in primary health care settings where such data may be important.

Effect of Harvest Date on Kernel Quality and Antioxidant Activity in su1 Sweet Corn Genotypes

In order to achieve a high-quality product, sweet corn should be harvested at the optimal stage of maturity. The taste of sweet corn depends largely on the kernel moisture (KM) and total sugars (TS) content while its health properties are attributed to the content of total phenols (TPH) and antioxidant activity (AO). This study aimed to estimate quality in sugary (su1) sweet corn hybrids based on the maximum content of kernel chemical compounds and the content change during maturation. During two growing seasons, five harvests by year were made at 2-day intervals from 17 to 25 days after pollination (DAP). KM decreased among hybrids from 6.6% to 14% over an eight-day period, or 0.8% to 1.8% per day. TS content was the highest at 17 DAP (16.5–28.7 mg/g DW) and decreased during maturation from 27% to 67%. Hybrids differed significantly in TPH at 17 DAP (204.4–357.1 mg GAE/100 g DW). TPH change during maturation ranged from the no significant differences up to a 29.3% decrease. DPPH- radical scavenging activity ranged among genotypes from 52.5% to 74.9% inhibition at 17 DAP and significantly increased during maturation. A well-defined hybrid-specific harvest window is necessary to maintain kernel quality in su1 sweet corn.

MO086: Sex Differences in Ambulatory Blood Pressure Trajectories and Blood Pressure Variability in Hemodialysis Patients

Abstract BACKGROUND AND AIMS Ambulatory blood pressure (BP) control is worse in men than in women with chronic kidney disease (CKD), and this may partially explain the faster CKD progression in men. The aim of this study is to investigate possible sex-differences in ambulatory BP levels, BP trajectories and BP variability (BPV) in hemodialysis patients. METHOD 129 male and 91 female hemodialysis patients that underwent 48-h ABPM with Mobil-O-Graph-NG were included in this analysis. Ambulatory BP levels over the 2-day interdialytic interval (including two daytime and two nighttime periods) were recorded. We calculated the standard deviation (SD), weighted SD (wSD), coefficient of variation (CV) and average real variability (ARV) of BP with validated formulas. RESULTS Age, dialysis vintage, antihypertensive treatment and history of major comorbidities did not differ between men and women. Pre-dialysis SBP levels did not differ between men and women (145.1 ± 22.7 versus 145.9 ± 25.7 mmHg, P = 0.808), but DBP was marginally higher in men (87.6 ± 14.0 versus 84.0 ± 13.7 mmHg, P =0.055). About 48-h SBP/DBP (137.2 ± 17.4/81.9 ± 12.1 mmHg versus 132.2 ± 19.2/75.9 ± 11.7 mmHg, P = 0.045/<0.001) as well as DBP during the first and SBP/DBP during the second 24-h period were significantly higher in men than in women. Similarly, daytime SBP/DBP was significantly higher in men (138.3 ± 17.5/83.2 ± 12.3 mmHg versus 131.9 ± 19.4/76.4 ± 11.5 mmHg, P = 0.011/<0.001). No significant between-group differences were detected for nighttime SBP. All SBP variability indices were similar between men and women; DBP-SD, DBP-wSD and DBP-ARV were higher in men (44-h DBP-ARV 9.4 ± 1.8 versus 8.6 ± 1.9, P = 0.002). No significant differences were revealed in the dipping pattern between men and women. CONCLUSION Ambulatory BP levels and trajectories, as well as DBP variability indices are higher in men than women hemodialysis patients. This worse ambulatory BP profile in male compared to female patients may impact on the incidence of cardiovascular events.

Replacing fish oil with crude palm oil in the diet of larval hybrid lemon fin barb (Barbonymus gonionotus ♀ × Hypsibarbus wetmorei ♂)

Hybrid lemon fin barb is a novel carp species produced in Malaysia crossing lemon fin barb (Hypsibarbus wetmorei, ♂) and silver barb (Barbonymus gonionotus, ♀). As the delicious wild H. wetmorei is being overexploited, this new hybrid species is produced, filling the production gap in Malaysian aquaculture. The hybrid larvae in our previous study showed high tolerance to bacterial diseases and revealed the suitability of culturing hybrid lemon fin barb in the tropics. The effects of increasing dietary replacements level of fish oil (FO) with crude palm oil (CPO) were investigated for the larval stage of this fast-growing and delicious carp species. Three-day old hybrid larvae were randomly allocated to fifteen 5-L tanks stocked at the rate of 50 larvae L−1. Five micro diets containing 0%, 25%, 50%, 75% and 100% dietary substitution levels of FO with CPO levels were formulated. An extra replicate tank was maintained for each treatment for enzyme sampling at 4-day intervals. After 20 days of the feeding trial, dietary replacement of FO with CPO did not significantly affect (p > 0.05) survival and growth of hybrid lemon fin barb larvae. Dietary CPO reduced (p < 0.05) docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) in hybrid larval tissues. Partial replacement of FO with CPO in hybrid lemon fin barb diets showed no lipid vacuoles in the liver and gut during the challenge test against A. hydrophila. In conclusion, total replacement of FO with CPO is acceptable for the culture of hybrid lemon fin barb larvae; though considering the health status of larvae, 75% replacement of dietary FO with CPO would be more applicable. However, lipid metabolism seems low at the early larval period in larvae fed dietary CPO.

Effects on Photosynthetic Response and Biomass Productivity of Acacia longifolia ssp. longifolia Under Elevated CO2 and Water-Limited Regimes.

It is known that the impact of elevated CO2 (eCO2) will cause differential photosynthetic responses in plants, resulting in varying magnitudes of growth and productivity of competing species. Because of the aggressive invasive nature of Acacia longifolia ssp. longifolia, this study is designed to investigate the effect of eCO2 on gas exchange parameters, water use efficiency, photosystem II (PSII) activities, and growth of this species. Plants of A. longifolia ssp. longifolia were grown at 400 ppm (ambient) and 700 ppm (elevated) CO2 under 100 and 60% field capacity. Leaf gas exchange parameters, water use efficiency, intrinsic water use efficiency, instantaneous carboxylation efficiency, and PSII activity were measured for 10 days at 2-day intervals. eCO2 mitigated the adverse effects of drought conditions on the aforementioned parameters compared to that grown under ambient CO2 (aCO2) conditions. A. longifolia, grown under drought conditions and re-watered at day 8, indicated a partial recovery in most of the parameters measured, suggesting that the recovery of this species under eCO2 will be higher than that with aCO2 concentration. This gave an increase in water use efficiency, which is one of the reasons for the observed enhanced growth of A. longifolia under drought stress. Thus, eCO2 will allow to adopt this species in the new environment, even under severe climatic conditions, and foreshadow its likelihood of invasion into new areas.

Nano-emulsion of mangosteen rind extract in a mucoadhesive patch for periodontitis regenerative treatment: An in vivo study

ObjectiveTo investigate the therapeutic potential of nano-emulsion of mangosteen rind extract in a mucoadhesive gingival patch on periodontitis, and its effect on tumor necrosis factor alpha (TNF-α), receptor activator of nuclear factor kappa Β ligand (RANKL), and interleukin 10 (IL-10) expression. MethodsSixty Wistar rats were divided into four groups: positive control group (mucoadhesive patch with doxycycline), negative control group (mucoadhesive patch), treatment group I (mucoadhesive patch with mangosteen rind extract), and treatment group II (mucoadhesive patch with nano-emulsion of mangosteen rind extract). An experimental model of Porphyromonas gingivalis-induced periodontitis was established in rats by treatment with 0.03 mL bacteria locally (1 × 1010 colony-forming units) seven times at 2-day intervals in the gingival sulcus of mandibular anterior teeth. Treatment was 1 h/day for 3 days. On days 3, 5, and 7, five rats from each group were killed. TNF-α, IL-10, and RANKL expression was determined by dissecting the lower jaw for immunohistochemistry. ResultsThe mucoadhesive patch with nano-emulsion mangosteen rind extract significantly decreased TNF-α and RANKL expression and increased IL-10 expression (p < 0.05) compared to the treatment I, positive and negative control groups. ConclusionA mucoadhesive gingival patch with nano-emulsion of mangosteen rind extract has the potential to treat periodontitis by decreasing TNF-α, RANKL, and increasing IL-10 expression.

Comparison of growth performance, survival rate and economic efficiency of Asian seabass (Lates calcarifer) intensively cultured in earthen ponds with high densities

This trial aimed to assess the impacts of high stocking densities on growth performance, survival rate and economic efficiency of Asian seabass (Lates calcarifer) intensively cultured in earthen ponds. The experiment was designed with three treatments of stocking density of 6, 8 and 10 fish m−2. Each treatment was replicated three times. Fish with an initial length of 11.7 ± 0.5 cm and weight of 22.1 ± 1.3 g was stocked in earthen ponds with area of 1000 m2 and water depth of 2.0 m. The fish was fed with pelleted feed containing 43–44% crude protein. Water quality parameters including temperature, dissolved oxygen, pH, salinity, transparency and ammonia concentration were measured once a week. The fish were sampled for length and weight measurement at every 30-day interval. Costs were recorded for economic efficiency estimation. Results of the study showed that the water quality parameters were in suitable ranges for the growth and development of Asian seabass. There was no significant difference (p > 0.05) between means of final length, survival rate and feed conversion ratio of the treatments. However, the growth in final weight and daily weight gain of the fish with the stocking of 6 fish m−2 was significantly higher (p < 0.05) compared to the stocking of 10 fish m−2. The benefit of the treatments of 8 and 10 fish m−2 were higher compared to the treatment of 6 fish m−2 but the highest capital efficiency was recorded for the treatment of 6 fish m−2.

Validity and reliability of performance tests as balance measures in patients with total knee arthroplasty

PurposeThis study aimed to investigate validity and reliability of the Timed Up and Go Test (TUG), 10 Meter Walk Test (10MWT), Single Leg Stance Test (SLST), 2 Minute Walk Test (2MWT), and Five Times Sit-to-Stand Test (5xSST) for evaluating balance in patients with total knee arthroplasty (TKA).Materials and MethodsThis cross-sectional study included 41 participants who had undergone TKA 6 months before the study due to osteoarthritis. Participants performed the TUG, 10MWT, SLST, 5xSST, and 2MWT. Each of the tests was performed twice, with a 1-day interval between tests. Intraclass correlation coefficient (ICC) models were used to determine the test–retest reliability. The level of correlations between performance tests and Berg Balance Scale and Fall Efficacy Scale-International were used to establish concurrent and convergent validity of the performance tests, respectively.ResultsThe mean age of the subjects was 64.07 ± 10.57 years. All tests showed excellent reliability (ICC > 0.94), excluding SLST that demonstrated good test–retest reliability (ICC = 0.72). All of the tests (SLST, 10MWT, 5xSST, 2MWT, TUG) were found to have good validity (rho > 0.704).ConclusionsAccording to these results, TUG, 10MWT, SLST, 5xSST, and 2MWT are reliable and valid outcome measures in patients with TKA, and could be used to assess balance after TKA surgery.

Changes on Sugar and Starch Contents during Seed Development of Synergistic Sweet Corn and Implication on Seed Quality

Synergistic sweet corn equipped with multiple-recessive genes encoding sugar synthesis is proposed through hybrid breeding to improve the balance eating quality including flavor, texture, and aroma. However, the drawback on seed quality occurs such as low germination and poor seedling vigor. This study aimed to investigate the changes of carbohydrate contents on seed quality of five sweet corn genotypes differing in the number of equipped recessive genes during seed development. Seeds were sampled at 4-day intervals from 18 to 46 days after pollination (DAP) and analyzed for seed germination, sugar, water-soluble polysaccharide, and starch. Then, their relationships were analyzed by using time series regression analysis. Although there were significant differences among 5 corn genotypes in their seed germination and carbohydrate contents, some genotypes showed responses in similar patterns. The optimal time to harvest seeds was genotype-dependent, which were 38 DAP for triple-recessive gene (btbtsh2sh2wxwx) and single-recessive genes (BtBtsh2sh2WxWx and Sh2Sh2susuWxWx) and 42 DAP for double-recessive genes (BtBtsh2sh2wxwx). The regression analysis revealed that seed germinability could be predicted by total starch content in synergistic sweet corn lines during seed development stages; however, this prediction seemed to be negligible in sweet corn genotypes equipped with a single-recessive gene. Implications and further suggestions for establishing an effective seed production technique and seed quality of synergistic sweet corn are discussed.

Outpatient Opioid Prescribing Habits in Pediatric Patients With Bone Sarcomas After Undergoing Primary Tumor Resection.

The majority of children with bone sarcomas experience pain. Opioids remain the mainstay treatment of cancer-related pain in children. The patterns of outpatient opioid prescription after surgery for primary bone sarcomas remains unknown. The purpose of this study is to evaluate the patterns of outpatient opioid prescription in patients with bone sarcomas after resection of the primary tumor, and to assess for factors that may lead to increased opioid dosing in these patients. A retrospective chart review of 28 patients with bone sarcomas undergoing primary tumor resection was performed. Demographic, medical, surgical, and pharmacological data was collected from all patients. The total morphine milligram equivalents (MMEs) prescribed after patient discharge were compared at 30-day intervals. The MMEs were then stratified by tumor location, presence of metastasis at time of surgery, and preoperative opioid use. Independent predictors of increased 30-day and total 120-day opioid utilization were evaluated. Patients with preoperative opioid use were prescribed significantly more opioids in every 30-day postoperative interval and for the 120-day total. When stratified by tumor location, patients with primary tumors in the pelvis had significantly greater postoperative opioid utilization when compared with patients with tumors located in the lower and upper extremities during postoperative days 61 to 90 (5970 vs. 1060.4 and 0 MMEs, respectively, P=0.048) and during postoperative days 91 to 120 (6450 vs. 829.6 and 0 MMEs, respectively, P=0.015). Older age, diagnosis of osteosarcoma, increased length of stay postoperatively and presence of metastases were associated with a higher 30-day postoperative opioid utilization. Multiple factors were associated with increased opioid use including preoperative opioid use, longer postoperative stay in the hospital, metastatic disease, and primary sarcomas in the pelvis. The patient's sex, body mass index, race, type of insurance, type of surgery performed, reoperation during the same admission and use of nonopioid adjuvants had no effect on opioid use. The results of this study can be used to stratify the average opioid requirement of pediatric patients undergoing primary bone sarcoma resection. Level IV.

Utility of a Deep Learning Algorithm for Detection of Reticular Opacity on Chest Radiography in Patients With Interstitial Lung Disease.

BACKGROUND. Deep learning has been heavily explored for pulmonary nodule detection on chest radiographs. Detection of reticular opacity in interstitial lung disease (ILD) is challenging and may also benefit from a deep learning algorithm (DLA). OBJECTIVE. The purpose of this study was to evaluate the utility of a DLA for detection of reticular opacity on chest radiographs of patients with surgically confirmed ILD. METHODS. This retrospective study included 197 patients (130 men, 67 women; mean age, 62.6 ± 7.6 [SD] years) with surgically proven ILD between January 2017 and December 2018 who underwent preoperative chest radiography and chest CT within a 30-day interval. A total of 197 age- and sex-matched control patients with normal chest radiographs were randomly selected. A commercially available DLA was used to detect lower lobe or subpleural abnormalities; those matching the reticular opacity location on CT were deemed true-positive. Six readers (three thoracic radiologists, three residents) independently reviewed radiographs with and without the DLA for the presence of reticular opacity. Interobserver agreement was assessed. Diagnostic performance was compared among interpretations. Subanalysis was performed according to CT-based classification of the severity of reticular opacity. Performance of the DLA was also assessed on 102 chest radiographs from a second institution (51 patients with ILD, 51 matched patients in the control group). RESULTS. Interobserver agreement was moderate (κ = 0.517) for readers alone and almost perfect (κ = 0.870) for readers using the DLA. Sensitivity, specificity, and accuracy of the DLA for reticular opacity were 98.0%, 99.0%, and 98.5%; of pooled readers alone were 77.3%, 92.3%, and 84.8%; and of readers using the DLA were 93.8%, 97.3%, and 95.6%. All metrics were significantly better (all p ≤ .002) for the DLA and for readers using the DLA than for readers alone. Sensitivity for readers without and with the DLA were 66.7% and 86.8% for mild disease, 84.2% and 98.8% for moderate disease, and 87.3% and 100.0% for severe disease. The DLA had 100.0% accuracy at the second institution. CONCLUSION. The DLA outperformed readers in detection of reticular opacity, and use of the DLA improved reader performance and interobserver agreement. The benefit of the DLA was more notable in sensitivity than in specificity and was maintained in mild disease. CLINICAL IMPACT. Use of the DLA may facilitate detection of reticular opacity on chest radiographs in the early stages of ILD.

Effect of capsular bend on the rotational stability of toric intraocular lens.

To assess the effect of capsular bend and axial length on the rotational stability of toric IOL. The prospective study included patients with preexisting astigmatism that were implanted with Acrysof IQ Toric IOL. According to the pre‑operative axial length, all patients were divided into 2 groups: high myopia (AL ≥ 26 mm) group, and emmetropia or low to moderate myopia group (AL <26 mm). High-speed Swept-source Optical Coherence Tomography (SS-OCT) radial scanning was performed after pupil dilation to obtain the toric IOL axial orientation and capsular bending index (CBI) at 1-day, 1-week, 1-month and 3-month intervals postoperatively. The correlation between the rotation of toric intraocular lens and the axial length or CBI was subsequently analyzed. 68 eyes of 57 patients were included in the research. The rotation of toric IOL within the high myopia group was greater than the control group (P = 0.001, 1month postoperative). Capsular contact with the IOL was delayed in highly myopic eyes, although the results were not statistically significant (P = 0.094, 1-month postoperatively). There was a positive correlation between the degree of rotation and axial length at the interval found between 1-week and 1-month after the operation (r = 0.333, P = 0.005). There was a significant negative correlation between the IOL rotational speed and CBI (P < 0.001). The regression equation was Y = -0.441*X + 1.712 (R2 = 0.323, P < 0.001). There was a significant negative correlation between the IOL rotation speed and the CBI, while the influence of the axial length and capsular bending mainly occurred between one week and one month after the operation.

Repetitive transcranial magnetic stimulation for patients with functional paralysis: a randomized controlled study.

Repetitive transcranial magnetic stimulation (rTMS) has been proposed to treat functional neurological disorders. Here, the aim was to assess the efficacy of rTMS to treat functional paralysis in a controlled randomized trial. Patients received two sessions of active or sham 0.25Hz rTMS (60 stimuli each), with a 1-day interval, applied over the motor cortex contralateral to the paralysis. The primary outcome was the number of patients with an increase in motor score between baseline and after the second rTMS session, rated by two investigators blinded to the treatment allocation. Secondary outcomes were changes in global and fine motor scores between groups after rTMS, and the occurrence of adverse events. Sixty-two patients (46 female; mean [SD] age, 35.2 [13.9] years) were enrolled and randomized. Thirteen out of 32 (41%) and 11/30 (37%) patients had increased motor strength after active or sham rTMS, respectively (p=0.80). Changes in both global and fine motor scores after rTMS relative to baseline were also not significantly different between treatment groups (median difference in the global motor score 0.62 [0.83] and 0.37 [0.61], and in the fine motor scores 0.12 [0.18] and 0.08 [0.11], in active and sham rTMS groups, respectively; p=0.14). Six serious adverse events, consisting of three cephalalgia in the active group and two cephalalgia and one asthenia in the sham group, were observed. Two sessions of sham or active low frequency rTMS were effective to improve functional paralysis, suggesting a placebo effect of this non-invasive brain stimulation technique.

Lag effects in grammar learning: A desirable difficulties perspective

AbstractThis paper examined lag effects in the learning of second language (L2) grammar. Moreover, following the Desirable Difficulty Framework for L2 practice, the present study investigated whether lag effects could be explained by other sources of difficulty. Using digital flashcards, 117 English language learners (aged 10–18) learned two grammatical structures over two different sessions at a 1-day or 7-day intersession interval (ISI). Learners’ performance was analyzed at two retention intervals (RIs) of 7 and 28 days, respectively. Linguistic difficulty was compared by examining two different structures, while learner-related difficulty was analyzed by comparing learners who differed in terms of age, proficiency, and time required to complete the training. Results showed no main effect of ISI, a main effect of RI, and a small but significant ISI × RI interaction. Linguistic difficulty and age did not interact with ISI or RI. However, longer lags led to significantly higher scores for faster learners and learners of higher proficiency, while shorter lags promoted significantly higher scores for slower learners and learners of lower proficiency. The findings provide some support for the Desirable Difficulty Framework in its potential to explain L2 lag effects.

Repeated low doses of LSD in healthy adults: A placebo-controlled, dose-response study.

The resurgence of interest in using psychedelic drugs, including lysergic acid diethylamide (LSD), in psychiatry has drawn attention to the medically unsupervised practice of 'microdosing'. Thousands of users claim that very low doses of LSD, taken at 3-4-day intervals, improve mood and cognitive function., However, few controlled studies have described the effects of the drug when taken in this way. Here, in a double-blind controlled study, we studied the effects of four repeated doses of LSD tartrate (13 or 26 μg) or placebo, administered to healthy adults at 3-4day intervals, on mood, cognitive performance and responses to emotional tasks. Participants were randomly assigned to one of three drug conditions: placebo (N = 18), 13 μg LSD (N = 19), or 26 μg LSD (N = 19). They attended four 5-hour drug-administration sessions separated by 3-4days, followed by a drug-free follow-up session 3-4days after the last session. LSD (26 μg) produced modest subjective effects including increased ratings of 'feeling a drug effect' and both stimulant-like and LSD-like effects, but the drug did not improve mood or affect performance on psychomotor or most emotional tasks. No residual effects were detected on mood or task performance on the drug-free follow-up session. We conclude that within the context of a controlled setting and a limited number of administrations, repeated low doses of LSD are safe, but produce negligible changes in mood or cognition in healthy volunteers.

A first-in-human phase 1b study of a novel allosteric extracellular FGFR2 inhibitor alofanib in patients with refractory metastatic gastric cancer.

304 Background: FGFR2 promotes gastric cancer progression, suggesting that inhibition of FGFR2 may be an important therapeutic strategy. Alofanib (RPT835) is a small molecule, allosteric inhibitor that binds to the non-active extracellular site of IIIc and IIIb FGFR2 isoforms with IC50 &lt; 10 nM. Methods: RPT835GC1B is a Phase 1b open-label study evaluating the safety and preliminary efficacy of alofanib in patients with metastatic gastric adenocarcinoma pretreated with ≥ 1 previous lines of therapy. The standard dose-escalation part (design 3+3) aimed to establish the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) as a primary endpoint. Secondary endpoints included pharmacokinetic (PK) parameters, rate of adverse events, progression-free survival (PFS), overall survival (OS), and objective response rate (ORR). Alofanib was administered daily intravenously for 5-days followed by a 2-day interval (rest). There were five dose levels: 50, 100, 165, 250, and 350 mg/m2. All patients received alofanib until disease progression or unacceptable toxicity. Results: As of 20 September 2021, 21 patients have been enrolled in the study. Patients were Caucasian (100%), predominantly male (71%), 67% had 2 and more metastatic sites, including liver metastases (43%), 14% had ECOG PS 2, and were heavily pretreated (86% had previous 3 and more lines of therapy). All enrolled patients have been studied for safety and have not experienced any dose-limiting toxicities (DLTs) within the 28-day DLT-assessment window. 17 (81%) patients had at least one treatment-related adverse event (trAE). Grade 3 or higher trAEs (5/23.8%) have included raised ALT/AST at 50 mg/m2, neutropenia at 50 mg/m2, diarrhea at 165 mg/m2, headache at 165 mg/m2, increased serum amylase at 350 mg/m2, and reactions immediately after intravenous injections (facial flushing, dizziness, weakness, sweating, and sinus tachycardia) at 350 mg/m2. Three (14.3%) patients discontinued treatment due to trAEs. Most common Grade 1-2 adverse events included reactions immediately after intravenous injections, diarrhea, thrombocytopenia, arthralgia, and headache. Grade 1 hyperphosphatemia was found in 1 (4.8%) patient. Table summarizes efficacy data. Conclusions: The MTD has not been reached and dose of 350 mg/m2 has been declared as RP2D. Alofanib showed acceptable tolerability and preliminary signs of clinical activity in the late-line treatment of metastatic gastric cancer. Clinical trial information: NCT04071184. [Table: see text]

Merlin Parental Behavior and Chick Development as Revealed by Webcam

Previous knowledge of the Merlin’s (Falco columbarius) nesting behavior was based on observation from the ground or data recorded during nest checks. Similarly, descriptions of chicks’ behavioral development were restricted to studies of captive birds. We used a webcam to observe adult Prairie Merlins (F. c. richardsonii) and their four young on an artificial nest platform located in Weyburn, Saskatchewan, from 25 April to 22 July 2020. Our observations extended from prior to egg-laying until 12 days after fledging, being most intensive after hatching. Activities revealed by the webcam largely confirmed previous ground-based observations and studies involving either nest visits or captive rearing. Eggs were laid at roughly 2-day intervals followed by a 30-day incubation period and a 31-day nestling period. The female dominated activity at the nest until the chicks achieved homeothermy (7–10 days after hatching); the male was seldom seen except when delivering prey to the female. The female stopped brooding chicks during the night after day 14 and during daylight on day 16. The male began bringing food directly to the chicks starting 17 days after hatching. The chicks’ development matched published reports with constant competition for food among chicks but also apparent efforts by the adult female to ensure that each chick received sufficient food. The webcam enabled us to gather more detailed information about the Merlin’s behavior at the nest than previously possible and provided an opportunity for citizen science involving a common but little studied falcon.