Biodistribution and internal radiation dosimetry of a companion diagnostic radiopharmaceutical, [68Ga]PSMA-11, in subcutaneous prostate cancer xenograft model mice

Abstract[68Ga]PSMA-11 is a prostate-specific membrane antigen (PSMA)-targeting radiopharmaceutical for diagnostic PET imaging. Its application can be extended to targeted radionuclide therapy (TRT). In this study, we characterize the biodistribution and pharmacokinetics of [68Ga]PSMA-11 in PSMA-positive and negative (22Rv1 and PC3, respectively) tumor-bearing mice and subsequently estimated its internal radiation dosimetry via voxel-level dosimetry using a dedicated Monte Carlo simulation to evaluate the absorbed dose in the tumor directly. Consequently, this approach overcomes the drawbacks of the conventional organ-level (or phantom-based) method. The kidneys and urinary bladder both showed substantial accumulation of [68Ga]PSMA-11 without exhibiting a washout phase during the study. For the tumor, a peak concentration of 4.5 ± 0.7 %ID/g occurred 90 min after [68Ga]PSMA-11 injection. The voxel- and organ-level methods both determined that the highest absorbed dose occurred in the kidneys (0.209 ± 0.005 Gy/MBq and 0.492 ± 0.059 Gy/MBq, respectively). Using voxel-level dosimetry, the absorbed dose in the tumor was estimated as 0.024 ± 0.003 Gy/MBq. The biodistribution and pharmacokinetics of [68Ga]PSMA-11 in various organs of subcutaneous prostate cancer xenograft model mice were consistent with reported data for prostate cancer patients. Therefore, our data supports the use of voxel-level dosimetry in TRT to deliver personalized dosimetry considering patient-specific heterogeneous tissue compositions and activity distributions.

Auditory Feedback Is Used for Adaptation and Compensation in Speech Timing

Purpose Real-time altered feedback has demonstrated a key role for auditory feedback in both online feedback control and in updating feedforward control for future utterances. The aim of this study was to examine adaptation in response to temporal perturbation using real-time perturbation of ongoing speech. Method Twenty native English speakers with no reported history of speech or hearing disorders participated in this study. The study consisted of four word blocks, using the phrases “a capper,” “a gapper,” “a sapper,” and “a zapper” (due to issues with the implementation of perturbation, “gapper” was excluded from analysis). In each block, participants completed a baseline phase (30 trials of veridical feedback), a ramp phase (feedback perturbation increasing to maximum over 30 trials), a hold phase (60 trials with perturbation held at maximum), and a washout phase (30 trials, feedback abruptly returned to veridical feedback). Word-initial consonant targets (voice onset time for /k, g/ and fricative duration for /s, z/) were lengthened, and the following stressed vowel (/æ/) was shortened. Results Overall, speakers did not adapt the production of their consonants but did lengthen their vowel production in response to shortening. Vowel lengthening showed continued aftereffects during the early portion of the washout phase. Although speakers did not adapt absolute consonant durations, consonant duration was reduced as a proportion of the total syllable duration. This is consistent with previous research that suggests that speakers attend to proportional durations rather than absolute durations. Conclusion These results indicate that speakers actively monitor proportional durations and update the temporal dynamics of planning units extending beyond a single segment.

Auditory feedback is used for adaptive control of timing in speech

Real-time altered auditory feedback has demonstrated a key role for auditory feedback in both online feedback control and in updating feedforward control for future utterances. Much of this research has examined control in the spectral domain, and has found that speakers compensate for perturbations to vowel formants, intensity, and fricative center of gravity. The aim of the current study is to examine adaptation in response to temporal perturbation, using real-time perturbation of ongoing speech. Word-initial consonant targets (VOT for /k, g/ and fricative duration for /s, z/) were lengthened and the following stressed vowel (/æ/) was shortened. Overall, speakers did not adapt to lengthened consonants, but did lengthen vowels by nearly 100\% of the perturbation magnitude in response to shortening. Vowel lengthening showed continued aftereffects during a washout phase when perturbation was abruptly removed. Although speakers did not actively adapt consonant durations, the adaptation in vowel duration leads to the consonant taking up an overall smaller proportion of the syllable, aligning with previous research that suggests that speakers attend to proportional durations rather than absolute durations. These results indicate that speakers actively monitor duration and update upcoming plans accordingly.

Reliability of Vibroarthrography to Assess Knee Joint Sounds in Motion

Knee acoustic emissions provide information about joint health and loading in motion. As the reproducibility of knee acoustic emissions by vibroarthrography is yet unknown, we evaluated the intrasession and interday reliability of knee joint sounds. In 19 volunteers (25.6 ± 2.0 years, 11 female), knee joint sounds were recorded by two acoustic sensors (16,000 Hz; medial tibial plateau, patella). All participants performed four sets standing up/sitting down (five repetitions each). For measuring intrasession reliability, we used a washout phase of 30 min between the first three sets, and for interday reliability we used a washout phase of one week between sets 3 and 4. The mean amplitude (dB) and median power frequency (Hz, MPF) were analyzed for each set. Intraclass correlation coefficients (ICCs (2,1)), standard errors of measurement (SEMs), and coefficients of variability (CVs) were calculated. The intrasession ICCs ranged from 0.85 to 0.95 (tibia) and from 0.73 to 0.87 (patella). The corresponding SEMs for the amplitude were ≤1.44 dB (tibia) and ≤2.38 dB (patella); for the MPF, SEMs were ≤13.78 Hz (tibia) and ≤14.47 Hz (patella). The intrasession CVs were ≤0.06 (tibia) and ≤0.07 (patella) (p < 0.05). The interday ICCs ranged from 0.24 to 0.33 (tibia) and from 0 to 0.82 (patella) for both the MPF and amplitude. The interday SEMs were ≤4.39 dB (tibia) and ≤6.85 dB (patella) for the amplitude and ≤35.39 Hz (tibia) and ≤15.64 Hz (patella) for the MPF. The CVs were ≤0.14 (tibia) and ≤0.08 (patella). Knee joint sounds were highly repeatable within a single session but yielded inconsistent results for the interday reliability.

Raspberries Improve Postprandial Glucose and Acute and Chronic Inflammation in Adults with Type 2 Diabetes

Background: Postprandial metabolic impairments in diabetes have been shown to play an important role in vascular complications. Dietary polyphenols and other bioactive compounds in berries have been shown to improve postprandial hyperglycemia and related metabolic impairments, but few clinical studies have been reported in diabetes. Objective: To examine the effects of daily dietary raspberries on postprandial and 4-week fasting glucose, lipids and biomarkers of inflammation in obese adults with type 2 diabetes. Design: This was a randomized crossover study with 2 different phases: a “postprandial phase” of acute raspberry supplementation (2 separate days at least 1 week apart), followed by a 1-week washout phase and then a 10-week “diet supplement phase”, with and without raspberry supplementation periods of 4 weeks each, separated by 2-week washout phase. Results: The postprandial phase revealed significantly lower levels of serum glucose at 2 and 4 h postprandial after raspberry versus control phase. In addition, among the serum biomarkers of inflammation, interleukin (IL)-6 and high-sensitivity tumor necrosis factor alpha (hsTNF-α) were also lower at 4 h postprandial following raspberry versus control meal (all p < 0.05). Finally, postprandial serum triglycerides showed a decreasing trend at 4 h in the raspberry versus control phase. Four-week daily raspberry supplementation continued to show a significant lowering effects on IL-6 and hsTNF-α versus control phase (all p < 0.05); systolic blood pressure revealed a decreasing trend after 4-week of raspberry supplementation. No effects were noted on fasting glucose and lipids, C-reactive protein and arterial elasticity. Conclusions: Thus, dietary raspberries, which are low in calories and high in polyphenols and other nutrients may lower postprandial hyperglycemia and inflammation, and in general exert selected anti-inflammatory effects in adults with diabetes. These findings deserve further investigation.

Algal and Vegetable Oils as Sustainable Fish Oil Substitutes in Rainbow Trout Diets: An Approach to Reduce Contaminant Exposure

The aim of this study was to replace 75% of total fish oil (FO) and alter digestible protein/digestible energy (DP/DE) in rainbow trout feeds to minimize potentially hazardous environmental contaminant exposure. Two diets differing in DP/DE ratios (18 and 25) were combined with soybean (SO), canola (CO), and a blend of canola oil and Schizochytrium sp. (COS). Dietary lipids and DP/DE ratios did not affect apparent digestibility, growth, and somatic parameters. The n-3/n-6 levels decreased significantly in the growth trial, especially for the SO groups. A short washout trial restored n-3/n-6 levels for the CO and COS groups, irrespective of the DP/DE ratio, but not for the SO groups. At all sampling events, contaminant concentrations in fish flesh were lower than limits set by regulatory agencies in Canada, the US, and Europe. Contaminants were lower in the oil replacement diets compared to FO for toxaphenes, organochlorine pesticides, and PCBs but not flame retardants during the growth phase. At the end of the washout phase, no differences were detected. Thus, this study revealed that replacing 75% of total fish oil in rainbow trout feed by CO and COS, combined with a 25 DP/DE ratio, with a washout period seems to be the most efficient approach in terms of maximizing the total FO replacement and contribute to reducing POPs exposure.

Improving hand hygiene compliance among healthcare workers in intensive care unit: an interventional study

Background: Hand hygiene (HH) is one of the most important measures to prevent healthcare-associated infections. The objective of the study was to assess the effectiveness of the augmented multi-interventional approaches on HH compliance rate among intensive care unit (ICU) healthcare workers (HCWs) of Farwaniya Hospital, Kuwait.Methods: An interventional study was conducted in four phases throughout eight months among adult ICU HCWs. First; HCWs, HH compliance rates and alcohol-based hand rub consumption rate (ABHR) were assessed secondly; an augmented multi-interventional approach was implemented, which included administrative support, observation and reporting, education & training, recruiting champions, and maintenance of HH supplies & reminders. Then a washout phase. Finally, re-assessment of HH compliance rates and ABHR.Results: Following the interventions, the overall HCWs’ HH compliance rate increased significantly from 58.81% to 73.17% (p=0.000), for doctors (39.82% vs. 64.93%) and nurses (68.24% vs. 80.18%), p>0.001. Significant improvement of HH compliance rates for most of HH moments, after moments were higher than before moments, p=0.000. ABHR increased significantly from 77.45 ml to 133.33 ml per patient day (95% CI=54.37-57.39, p<0.0001).Conclusions: The applied augmented multi-interventional approach was effective in improving HH compliance rates among ICU HCWs. Sustainability is warranted by continues implementation of this approach.

Dual RAAS Blockade with Aliskiren in Patients with Severely Impaired Chronic Kidney Disease

Dual renin-angiotensin-aldosterone blockade (dRAASb) is purposed in the prevention of the cardiorenal syndrome (CRS). However, all attempts with dRAASb even in patients with moderate impaired chronic kidney disease (CKD) were terminated due to the typical severe adverse events (SAE), e. g., hyperkalemia and rise of serum creatinine. The aim of our study with the direct renin inhibitor aliskiren was to evaluate the effect of dRAASb with a washout phase in patients with severely advanced CKD. We have studied 45 patients (G3b to 4, A2 and >A3; median glomerular filtration rate (GFR) CKD-EPI 31 (23–40) ml/min per 1.73 m² BSA (body surface area), albumin-creatinine-ratio in urine (UACR) (0.413 (0.164 to 1.39) g/g) and proteinuria (0.5 (0.2 to 0.9) g/l) before, with and without aliskiren (150 respectively 300 mg per day) added to an angiotensin-converting enzyme inhibitor (ACEi) or an AT1-receptor blocker (ARB) over 4 ½ years. The dRAASb with aliskiren showed a significant decrease of proteinuria (0.5 to 0.38 g/l), especially in patients with an UACR≥350 mg/g and in the subgroup analysis e. g., in patients with diabetes, but proteinuria increased in the washout phase again. The blood pressure (130/80 mm Hg), serum potassium (4.9 to 5.0 mmol/l) and GFR remained nearly constant (31 to 29.5 ml/min per 1.73 m2 BSA). A more than 30% increase in serum creatinine was associated with an UACR>300 mg/g. The dRAASb has beneficial effects on proteinuria and is safe in patients with severely advanced CKD. However, in patients with high UACR (>300 mg/g) raise of creatinine and potassium have to be controlled.

Vitamin D3supplementation in healthy adults: a comparison between capsule and oral spray solution as a method of delivery in a wintertime, randomised, open-label, cross-over study

Vitamin D is typically supplied in capsule form, both in trials and in clinical practice. However, little is known regarding the efficacy of vitamin D administered via oral sprays – a method that primarily bypasses the gastrointestinal absorption route. This study aimed to compare the efficacy of vitamin D3liquid capsules and oral spray solution in increasing wintertime total 25-hydroxyvitamin D (25(OH)D) concentrations. In this randomised, open-label, cross-over trial, healthy adults (n22) received 3000 IU (75 µg) vitamin D3daily for 4 weeks in either capsule or oral spray form. Following a 10-week washout phase, participants received the opposite treatment for a final 4 weeks. Anthropometrics and fasted blood samples were obtained before and after supplementation, with samples analysed for total 25(OH)D, creatinine, intact parathyroid hormone and adjusted Ca concentrations. At baseline, vitamin D sufficiency (total 25(OH)D>50 nmol/l), insufficiency (31–49 nmol/l) and clinical deficiency (<30 nmol/l) were evident in 59, 23 and 18 % of the participants, respectively. Overall, baseline total mean 25(OH)D concentration averaged 59·76 (sd29·88) nmol/l, representing clinical sufficiency. ANCOVA revealed no significant difference in the mean and standard deviation change from baseline in total 25(OH)D concentrations between oral spray and capsule supplementation methods (26·15 (sd17·85)v. 30·38 (sd17·91) nmol/l, respectively;F=1·044, adjustedr20·493,P=0·313). Oral spray vitamin D3is an equally effective alternative to capsule supplementation in healthy adults.