Trial Period Research Articles

Implementing Germ Defence digital behaviour change intervention via all primary care practices in England to reduce respiratory infections during the COVID-19 pandemic: an efficient cluster randomised controlled trial using the OpenSAFELY platform

BackgroundGerm Defence (www.germdefence.org) is an evidence-based interactive website that promotes behaviour change for infection control within households. To maximise the potential of Germ Defence to effectively reduce the spread of COVID-19, the intervention needed to be implemented at scale rapidly.MethodsWith NHS England approval, we conducted an efficient two-arm (1:1 ratio) cluster randomised controlled trial (RCT) to examine the effectiveness of randomising implementation of Germ Defence via general practitioner (GP) practices across England, UK, compared with usual care to disseminate Germ Defence to patients. GP practices randomised to the intervention arm (n = 3292) were emailed and asked to disseminate Germ Defence to all adult patients via mobile phone text, email or social media. Usual care arm GP practices (n = 3287) maintained standard management for the 4-month trial period and then asked to share Germ Defence with their adult patients. The primary outcome was the rate of GP presentations for respiratory tract infections (RTI) per patient. Secondary outcomes comprised rates of acute RTIs, confirmed COVID-19 diagnoses and suspected COVID-19 diagnoses, COVID-19 symptoms, gastrointestinal infection diagnoses, antibiotic usage and hospital admissions. The impact of the intervention on outcome rates was assessed using negative binomial regression modelling within the OpenSAFELY platform. The uptake of the intervention by GP practice and by patients was measured via website analytics.ResultsGerm Defence was used 310,731 times. The average website satisfaction score was 7.52 (0–10 not at all to very satisfied, N = 9933). There was no evidence of a difference in the rate of RTIs between intervention and control practices (rate ratio (RR) 1.01, 95% CI 0.96, 1.06, p = 0.70). This was similar to all other eight health outcomes. Patient engagement within intervention arm practices ranged from 0 to 48% of a practice list.ConclusionsWhile the RCT did not demonstrate a difference in health outcomes, we demonstrated that rapid large-scale implementation of a digital behavioural intervention is possible and can be evaluated with a novel efficient prospective RCT methodology analysing routinely collected patient data entirely within a trusted research environment.Trial registrationThis trial was registered in the ISRCTN registry (14602359) on 12 August 2020.

Amyloid‐beta immunotherapy induces novel methylomic changes in Alzheimer’s disease brain

AbstractBackgroundPost‐mortem neuropathological examinations following the first active immunotherapy strategy (AN‐1792, Elan Pharmaceuticals, 2000) for Alzheimer’s disease (AD) have evidenced amyloid‐β (Aβ) plaque clearance and increased microglial phagocytic activity in immunised individuals. This study characterises the epigenetic profiles of individuals who underwent Aβ immunotherapy with the aim of discovering novel therapeutic targets and biomarkers.MethodDNA was isolated from post‐mortem prefrontal cortex tissue of 16 immunised AD cases who received varying doses (ug) and number of doses during the trial period, including placebos. DNA methylation was quantified using methylation arrays and the raw intensity values processed and normalised for subsequent statistical analysis to identify differentially methylated positions (DMPs) across the genome associated with Aβ immunotherapy. Additional analyses included regions of enrichment analysis for identification of differentially methylated regions (DMRs) and weighted gene co‐expression network analysis to identify gene clusters with highly correlated methylation levels.ResultAfter correcting for known (age, sex, cell type composition) and unknown variables, a DMP located within Chromosome 19 Open Reading Frame 12 (C19Orf12) at the genome‐wide significance level (P < 9.00E−08) was associated with Aβ immunisation. 10 DMRs were further associated with immunisation, with three regions consisting of ≥ 3 CpG sites and having a Sidak‐corrected P < 0.05. These regions were located within the CRISP2 (chr6; 49681178:49681391 [8 probes], Sidak‐corrected P = 8.29E‐05), CTTNA1 (chr5; 138210906:138211184 [8 probes], Sidak‐corrected P = 5.96E‐06), and RNF39 (chr6; 30038859:30039025 [12 probes], Sidak‐Corrected P = 2.60E‐05) genes.ConclusionIndicating better inflammatory markers can help inform of effective preventative care strategies for elders. This study provides evidence for altered epigenetic processes in the pathophysiology of AD and identifies novel processes specific to Aβ immunotherapy. The next step for this project includes analysing RNA sequencing data, to determine if observed methylomic changes correlate with gene expression, and genotyping array data.

Middle Age Prevention of Future Alzheimer’s Disease and Related Dementias with Intensive Treatment of Hypertension: Middle PATH Clinical Trial Proposal

AbstractStrong epidemiological evidence from multiple studies suggests that elevated systolic blood pressure (SBP) in midlife is a risk factor for Alzheimer’s disease and Related Dementias (ADRD) later in life. The most common neuropathology of biomarker‐confirmed AD is combined AD neuropathological changes and cerebrovascular disease. Hypertension is a leading cause of cerebrovascular disease. The SPRINT MIND trial demonstrated that a goal SBP<120 mm Hg reduced risk for combined mild cognitive impairment (MCI) and dementia by 15% in older individuals compared to a goal SBP<140 mm Hg. SBP can be safely treated with inexpensive medications. Despite being potentially safe and cost‐effective, with strong supporting evidence for benefit, intensive SBP lowering in midlife to reduce future ADRD risk has never been studied, likely because clinical outcomes of MCI and dementia are not practical in this age range in a trial that is usually limited to about 5 years. Elevated SBP is a major risk factor for white matter hyperintensity volume (WMHV) accumulation, an MRI marker with extensive evidence demonstrating this to be associated with and predictive of incident ADRD, making WMHV a suitable surrogate outcome for the initial trial period. While we acknowledge the challenges of using a surrogate outcome, there is no suitable alternative when testing interventions to lower future ADRD risk starting in middle age, a strategy that we believe is essential. The Alzheimer’s Prevention Initiative and Wake Forest have formed a collaboration to investigate the effect of goal SBP<120 mm Hg compared to the SBP achieved by enhanced usual care (SBP = 135 mm Hg) on annualized rate of WMHV accumulation in persons ages 45‐65 who have some existing vascular risk at baseline. Secondary outcomes of changes in AD blood biomarkers and relevant cognitive test scores will help elucidate whether and how SBP and AD are interactive or independent deleterious pathophysiological processes. The intention, should the initial phase prove successful, is to continue and expand the trial until a clinical benefit can definitively be assessed.

Effect of Dietary Supplementation of Soybean Bioactive Peptides and Vitamin E on Productive Performance and Some Carcass Characteristics in Broiler Chickens

This study aimed at evaluating productive performance and some carcass characteristics of broiler chickens fed feeds containing different levels of soybean bioactive peptide (SBP), and vitamin E. 180 Ross-308 broiler chicks were divided equally into five treatments, each replicated three times, and twelve unsexed chicks were placed in each replicate in a completely randomized design. For a 35-day trial period, the basal diet was either supplied without supplements (control group), or it was supplemented with SBP at 2.5, 5.0, and 7.5 g/kg diet, or with vitamin E at 250 mg/kg feed. Results indicated that body weights at different ages were significantly (p≤0.05) higher in SBP groups during 2nd week (except 2.5 g/kg SBP), 3rd week, 4th week, and 5th week as compared with control and vitamin E groups. Gain in total body weight, ratio of feed conversion, and production index were improved significantly (P≤0.05) in SBP compared to other groups. The economic efficiency improved in the SBP and the vitamin E group than in control group. Feed intake, mortality rate, carcass yield, total giblets, total edible parts, liver, and heart yield were similar among groups. The highest (P≤0.05) carcass weight and breast yield were observed in the SBP than in other groups, while the gizzard relative weight in the vitamin E group achieved the highest significant value (3.22 %) as compared with SBP and control groups. Significant effect among treatment was observed in thigh yield. In compared to the control, 5 (g/kg) SBP showed the lowest (P≤0.05) abdominal fat percentage. The current findings suggested that the supplementation of broiler diets with SBP improved productive performance and some carcass traits.

Impact on End‐of‐life Planning of a Care Coordination Program for persons living with dementia

AbstractBackgroundAlzheimer’s disease and related dementias (ADRD) afflict over five million persons in the U.S., and persons living with dementia (PLWD) have been shown to receive poor quality care and have worse health outcomes compared to those without ADRD. We developed a population‐based dementia care management program to support the care of PWLD in a large U.S. healthcare system.MethodsIn a large multi‐specialty medical group practice, we identified patients enrolled in a value‐based insurance program (Medicare Advantage) using the EPIC electronic health record (EHR), and eligible patients were invited to enroll in the CARES dementia care program. Patients were eligible if they had an ICD‐10 diagnosis of ADRD in the EHR problem list and/or past medical history, or currently taking an FDA‐approved medication for ADRD. We additionally included patients with ADRD who have a primary care provider in the affiliated academic health system. During an in‐person intake visit, a study‐assigned nurse practitioner (NP) engaged in advance care planning discussion with patients and caregivers and completed advance directives (AD) and Physician Order for Life Sustaining Treatment (POLST). We assessed the rate of completion of the AD and POLST pre‐program and post‐enrollment.ResultsWe enrolled 195 patients in the CARES dementia care program. After enrollment, participants increased completion of advanced directives from 27.7% to 30.8% (p = 0.25) and the POLST from 13.3% to 23.1% (p = 0.006). Of the POLST forms completed, 70.7% indicated that the patient was ‘do not attempt resuscitation’ (DNAR) (65.2% of those who completed the POLST pre‐program, 77.8% for those who completed after enrollment, p = 0.19). Among those who completed the POLST, 55.0% indicated selective medical interventions (63.6% pre‐program, 47.1% post‐enrollment, p = 0.15), 40.0% wanted full medical interventions (31.8% pre‐program, 52.9% post‐enrollment, p = 0.10), and 5.0% wanted comfort‐focused interventions (4.5% pre‐program, 5.9% post‐enrollment, p = 0.43). Trial period of nutritional supports was indicated by 69.2% (72.7% pre‐program, 64.7% post‐enrollment, p = 0.28), while 28.2% wanted no artificial treatment (27.2% pre‐program, 29.4% post‐enrollment, p = 0.45), and 2.6% wanted long‐term nutritional support (0% pre‐program, 5.9% post‐enrollment, p = 0.13).ConclusionA dementia care coordination program shows signs of increased completion of end‐of‐life planning, with the majority choosing ‘do not attempt resuscitation’ (DNAR).

Middle Age Prevention of Future Alzheimer’s Disease and Related Dementias with Intensive Treatment of Hypertension: Middle PATH Clinical Trial Proposal

AbstractStrong epidemiological evidence from multiple studies suggests that elevated systolic blood pressure (SBP) in midlife is a risk factor for Alzheimer’s disease and Related Dementias (ADRD) later in life. The most common neuropathology of biomarker‐confirmed AD is combined AD neuropathological changes and cerebrovascular disease. Hypertension is a leading cause of cerebrovascular disease. The SPRINT MIND trial demonstrated that a goal SBP<120 mm Hg reduced risk for combined mild cognitive impairment (MCI) and dementia by 15% in older individuals compared to a goal SBP<140 mm Hg. SBP can be safely treated with inexpensive medications. Despite being potentially safe and cost‐effective, with strong supporting evidence for benefit, intensive SBP lowering in midlife to reduce future ADRD risk has never been studied, likely because clinical outcomes of MCI and dementia are not practical in this age range in a trial that is usually limited to about 5 years. Elevated SBP is a major risk factor for white matter hyperintensity volume (WMHV) accumulation, an MRI marker with extensive evidence demonstrating this to be associated with and predictive of incident ADRD, making WMHV a suitable surrogate outcome for the initial trial period. While we acknowledge the challenges of using a surrogate outcome, there is no suitable alternative when testing interventions to lower future ADRD risk starting in middle age, a strategy that we believe is essential. The Alzheimer’s Prevention Initiative and Wake Forest have formed a collaboration to investigate the effect of goal SBP<120 mm Hg compared to the SBP achieved by enhanced usual care (SBP≥135 mm Hg) on annualized rate of WMHV accumulation in persons ages 45‐65 who have some existing vascular risk at baseline. Secondary outcomes of changes in AD blood biomarkers and relevant cognitive test scores will help elucidate whether and how SBP and AD are interactive or independent deleterious pathophysiological processes. The intention, should the initial phase prove successful, is to continue and expand the trial until a clinical benefit can definitively be assessed.

RoboticScope-Assisted Microanastomosis in a Chicken Leg Model.

Background Many recent studies show that exoscopes are safe and effective alternatives to operating microscopes (OM). Developments of robotics and automation are present in neurosurgery with the appearance of a newer device such as RoboticScope (RS) exoscope with a digital three-dimensional (3D) image and a head-mounted display. The body of the RS is connected to a six-axis robotic arm that contains two video cameras, and serves as stereovision. This robotic arm allows accurate 3D camera motions over the field of view, giving the user a great degree of freedom in viewpoint selection. The surgeons may specify the direction and speed of the robotic arm using simple head movements when the foot pedal is pressed. Since its development in 2020, the RS has occasionally been used in neurosurgery for a multitude of procedures. Methods This study showcases vessel microanastomosis training on chicken legs using the RS. The aim of this study is to demonstrate the feasibility of the RS without a comparative analysis of the standard OM. The study was conducted in 2023 during a month-long trial period of the device at the Department of Neurosurgery of the Clinical Center of the University of Sarajevo. All procedures including RS-assisted anastomosis were performed by a neurosurgeon in anastomosis training (A.A.) supervised by a senior vascular neurosurgeon (E.B.). For the purpose of the study, we evaluated occlusion time in minutes, bypass patency with iodine, and overall satisfaction of the trainee in terms of light intensity, precision of automatic focus, mobility of the device, ergonomics, and convenience of the helmet. Results Ten RS-assisted microanastomoses were performed by interrupted suturing technique with 10.0 nylon thread. Bypass training included seven "end-to-side," two "end-to-end," and one "side-to-side" microanastomoses. The smallest vessel diameter was 1 mm. Occlusion time improved by training from 50 to 24 minutes, with contrast patency of the anastomoses in all cases without notable leakage of the contrast, except one case. Complete satisfaction of the trainee was achieved in 7 out of 10 cases. During this period, we also performed different RS-assisted surgeries including a single indirect bypass, convexity brain tumor resection, and microdiscectomies. Conclusion RS provides a new concept for microanastomosis training as an alternative or adjunct to the standard microscope. We found a full-time hands-on microsuturing without the need for manual readjustment of the device as an advantage as well as instant depth at automatic zooming and precise transposition of the focus via head movements. However, it takes time to adapt and get used to the digital image. With the evolution of the device helmet's shortcomings, the RS could represent a cutting-edge method in vessel microanastomosis in the future. Nevertheless, this article represents one of the first written reports on microanastomosis training on an animal model with the above-mentioned device.

Effect of Age Range on Power for a Clinical Trial Investigating the Effect of Intensive Systolic Blood Pressure Control on White Matter Hyperintensity Volume Accumulation

AbstractBackgroundEpidemiological evidence has repeatedly demonstrated elevated systolic blood pressure (SBP) in midlife as a modifiable risk factor for Alzheimer’s Disease and Related Dementia (ADRD) later in life. Despite SBP being readily treatable with safe and inexpensive medications, no clinical intervention implementing a lower SBP goal (<120 mm Hg) in midlife to lower future ADRD risk has ever been attempted. Clinical outcomes are not practical in the age range of interest (45‐65 or 45‐70) during an initial trial period of 5 years however robust evidence demonstrates white matter hyperintensity volume (WMHV) as an MRI finding associated with and predictive of incident ADRD.MethodWe used four data sets (SPRINT, Wisconsin Registry for Alzheimer’s Prevention, Framingham, and UK Biobank) with longitudinal MRI data to examine the effect of age range on power for a clinical trial proposal investigating the effect of intensive SBP control on annualized rates of WMHV accumulation in persons starting in middle age. Analyses were conducted separately in each data set. We calculated mean, standard deviations, and annualized rates of WMHV accumulation (derived from T2 FLAIR MRI), using the linear rate of change for accumulation rate, first stratifying by SBP ( = 132 mm Hg vs <132mm Hg except in SPRINT where groups were stratified by goal SBP group) and then by various age ranges. Next, we examined the effect of age range on necessary sample size with 80% power and two‐tailed alpha of 0.05 for a prospective clinical trial.ResultAs expected, annualized WMHV accumulation rate is lower with younger age in all data sets. However, variability decreased (all four data sets) and the percent reduction achieved at lower SBPs is higher at younger ages (3/4 data sets), thus increasing power when excluding older individuals (e.g., >65 years old, Table 1).ConclusionRestricting age to individuals to = 65 years‐old may unexpectedly increase power in a clinical trial designed to investigate the effect of goal SBP<120 mm Hg on annualized WMHV accumulation rate. 45‐65 years‐old is a practical age range for the first ever clinical trial intended to investigate the effects of a lower SBP goal in middle age to reduce future ADRD risk.

Replacing Soybean Meal with Azolla Plant as a Source of Protein on Performance of Iraqi Awassi Lambs

This study was executed in the animal field of the College of Agricultural Engineering Sciences at the University of Baghdad from November 15, 2022, to January 1, 2023. It was preceded by a 14-day trial period using 20 Awassi male lambs, whose ages ranged from 3.5 to 4 months. Moreover, starting with 18 to 19 kg. They were divided into four treatments at random: T1, which contained 6% soybeans and no azolla plant; T2, which contained 4% soybeans and 4% dry azolla plant; T3, which contained 2% soybeans and 8% dry azolla plant; and T4, which contained 12% dry azolla plant The results showed that there was a significant difference (p>0.05) in the daily and total weight gain as well as the digestion coefficient for some of the digested nutrients. Treatment T4 performed better than the other treatments in terms of increasing daily and total weight, while treatments T1 and T3 did not differ from each other The table of total nutrients digested and the field digestion coefficient did not change between the treatments T1 and 3T, which were better than treatment T2. There was no difference between treatment T1 and T3, which was superior to treatment T2, and there was a significant rise (P 0.05) for crude fiber and ether extract in treatment T4. The study found that adding 12% more Azolla plant to soybean meal resulted in the best weight growth and the highest digestibility of crude fiber and ether extract.

Effect of Age Range on Power for a Clinical Trial Investigating the Effect of Intensive Systolic Blood Pressure Control on White Matter Hyperintensity Volume Accumulation

AbstractBackgroundEpidemiological evidence has repeatedly demonstrated elevated systolic blood pressure (SBP) in midlife as a modifiable risk factor for Alzheimer’s Disease and Related Dementia (ADRD) later in life. Despite SBP being readily treatable with safe and inexpensive medications, no clinical intervention implementing a lower SBP goal (<120 mm Hg) in midlife to lower future ADRD risk has ever been attempted. Clinical outcomes are not practical in the age range of interest (45‐65 or 45‐70) during an initial trial period of 5 years however robust evidence demonstrates white matter hyperintensity volume (WMHV) as an MRI finding associated with and predictive of incident ADRD.MethodWe used four data sets (SPRINT, Wisconsin Registry for Alzheimer’s Prevention, Framingham, and UK Biobank) with longitudinal MRI data to examine the effect of age range on power for a clinical trial proposal investigating the effect of intensive SBP control on annualized rates of WMHV accumulation in persons starting in middle age. Analyses were conducted separately in each data set. We calculated mean, standard deviations, and annualized rates of WMHV accumulation (derived from T2 FLAIR MRI), using the linear rate of change for accumulation rate, first stratifying by SBP (≥132 mm Hg vs <132mm Hg except in SPRINT where groups were stratified by goal SBP group) and then by various age ranges. Next, we examined the effect of age range on necessary sample size with 80% power and two‐tailed alpha of 0.05 for a prospective clinical trial.ResultAs expected, annualized WMHV accumulation rate is lower with younger age in all data sets. However, variability decreased (all four data sets) and the percent reduction achieved at lower SBPs is higher at younger ages (3/4 data sets), thus increasing power when excluding older individuals (e.g., >65 years old, Table 1).ConclusionRestricting age to individuals to ≤65 years‐old may unexpectedly increase power in a clinical trial designed to investigate the effect of goal SBP<120 mm Hg on annualized WMHV accumulation rate. 45‐65 years‐old is a practical age range for the first ever clinical trial intended to investigate the effects of a lower SBP goal in middle age to reduce future ADRD risk.

Yeast culture repairs rumen epithelial injury by regulating microbial communities and metabolites in sheep.

This study delves into the impact of yeast culture (YC) on rumen epithelial development, microbiota, and metabolome, with the aim of investigating YC's mechanism in regulating rumen fermentation. Thirty male lambs of Hu sheep with similar age and body weight were selected and randomly divided into three groups with 10 lambs in each group. Lambs were fed a total mixed ration [TMR; rough: concentrate (R:C) ratio ≈ 30:70] to meet their nutritional needs. The experiment adopted completely randomized design (CRD). The control group (CON) was fed the basal diet with high concentrate, to which 20 g/d of YC was added in the low dose YC group (LYC) and 40 g/d of YC in the high dose YC group (HYC). The pretrial period was 14 days, and the experimental trial period was 60 days. At the end of a 60-day trial, ruminal epithelial tissues were collected for histomorphological analysis, and rumen microorganisms were analyzed by 16S rDNA sequencing and rumen metabolites by untargeted liquid chromatography-mass spectrometry (LC-MS) metabolomics techniques. The results showed that YC improved rumen papilla development and increased rumen papilla length (p < 0.05), while decreased cuticle thickness (p < 0.05). The 16S rDNA sequencing results showed that YC reduced the relative abundance of Prevotella_1 (p < 0.05), while significantly increased the relative abundance of Ruminococcaceae_UCG-005, uncultured_bacterium_f_Lachnospiraceae, and Ruminococcus_1 genus (p < 0.05). Metabolomics analysis showed that YC changed the abundance of metabolites related to amino acid metabolism, lipid metabolism and vitamin metabolism pathways in the rumen. In summary, YC might maintain rumen health under high-concentrate diet conditions by changing rumen microbiota structure and fermentation patterns, thereby affecting rumen metabolic profiles and repairing rumen epithelial injury.

Should I take aspirin? A qualitative study on the implementation of a decision aid on taking aspirin for bowel cancer prevention

ObjectivesAustralian guidelines recommend 50–70 years consider taking aspirin to reduce their bowel cancer risk. We trialled a decision aid in general practice to facilitate the implementation of these guidelines into...

EFFICIENCY OF SELENIUM-CONTAINING DRUG IN THE TREATMENT OF CALVES WITH SIGNS OF WHITE-MUSCULAR DISEASE

The article presents the results of clinical trials of veterinary medicinal selenium-containing drug in the treatment of calves with signs of white-muscular disease. The drug, a solution for oral use, was used in the recommended dosage for 5 days.&#x0D; Blood for laboratory research was selected from animals before and after application of the drug. Studies of hematological and biochemical parameters were conducted according to generally accepted methods. The therapeutic efficiency of the drug was evaluated by comparing with the data obtained before treatment and with the indicators of healthy animals of the control group. Based on the data obtained and their statistical analysis, the conclusion about drug’s effect on the morphofunctional state of calves’s body was made.&#x0D; Laboratory studies of the morphological parameters of calves’s blood with signs of a white-muscular disease in the period before use of the drug revealed significant deviations from the values of the physiological norm. The reliably lower content of hemoglobin, number of erythrocytes, leukocytes and the value of the hematocrit indicator, compared to the healthy calves of the control group, are established. The biochemical profile of calves’s serum was marked by its lower content of total protein, serum albumin and a lower concentration of Calcium, Phosphorus, Magnesium, as well as urea and creatinine content. At the same time, the activity of serum "muscle enzymes" – AST and CK was significantly higher, against the background of a reduced blood glucose content, which is a characteristic feature of white-muscular disease of calves.&#x0D; A comparative analysis of hematological indicators of calves after application of the drug showed activation of hematopoetic processes, which was confirmed by red blood indicators and normalization of the number of leukocytes and indicated the improvement of the physiological condition of animals. Serum biochemical indices of calves of the experimental group after treatment indicated a significant increase in the content of total protein, serum albumin and a significant decrease in the activity of "muscle enzymes" and the gradual normalization of serum glucose concentration. However, the difference in these indicators with the calves of the control group was still traced. Other biochemical parameters of calves of the experimental group did not differ reliably from the serum indicators of the control group.&#x0D; During the observation period, the clinical condition of sick calves has improved significantly. Clinical examination of animals of the experimental group after 2 weeks from the last drug application confirmed the absence of clinical signs of muscular dystrophy in calves. No side effects and negative phenomena in calves of the experimental group have been detected during the clinical trial period.

Effects of an Exercise Program to Reduce Falls in Older People Living in Long-Term Care: A Randomized Controlled Trial

ObjectivesTo investigate the effect of an exercise program on falls in intermediate and high-level long-term care (LTC) residents and to determine whether adherence, physical capacity, and cognition modified outcomes. DesignRandomized controlled trial. Setting and ParticipantsResidents (n = 520, aged 84 ± 8 years) from 25 LTC facilities in New Zealand. MethodsIndividually randomized to Staying UpRight, a physical therapist–led, balance and strength group exercise program delivered for 1 hour, twice weekly over 12 months. The control arm was dose-matched and used seated activities with no resistance. Falls were collected using routinely collected incident reports. ResultsBaseline fall rates were 4.1 and 3.3 falls per person-year (ppy) for intervention and control groups. Fall rates over the trial period were 4.1 and 4.3 falls ppy respectively [P = .89, incidence rate ratio (IRR) 0.98, 95% CI 0.76, 1.27]. Over the 12-month trial period, 74% fell, with 63% of intervention and 61% of the control group falling more than once. Risk of falls (P = .56, hazard ratio 1.08, 95% CI 0.85, 1.36) and repeat falling or fallers sustaining an injury at trial completion were similar between groups. Fall rates per 100 hours walked did not differ between groups (P = .42, IRR 1.15, 95% CI 0.81, 1.63). Program delivery was suspended several times because of COVID-19, reducing average attendance to 26 hours over 12 months. Subgroup analyses of falls outcomes for those with the highest attendance (≥50% of classes), better physical capacity (Short Physical Performance Battery scores ≥8/12), or cognition (Montreal Cognitive Assessment scores ≥ 18/30) showed no significant impact of the program. Conclusions/ImplicationsIn intermediate and high-level care residents, the Staying UpRight program did not reduce fall rates or risk compared with a control activity, independent of age, sex, or care level. Inadequate exercise dose because of COVID-19–related interruptions to intervention delivery likely contributed to the null result.

Effects of the Supplementation of Essential Oil Mixtures on Growth Performance, Nutrient Digestibility, Immune Status and Microbial Community in Weaned Piglets

Since essential oils—such as cinnamaldehyde, thymol, carvacrol, and eugenol—have antibacterial, antioxidant, and anti-inflammatory properties, this study aimed to examine the supplementation of different essential oil mixtures together with 1600 mg/kg zinc oxide (ZnO) on growth performance, incidence of diarrhea, serum immune indices, fecal volatile fatty acids, and microflora structure in weaned piglets. A total of 240 weaned piglets (Duroc × Landrace × Yorkshire) with an average body weight of 8.85 ± 0.21 kg were randomly allocated to 30 pens (6 pens per diet, 4 males and 4 females per pen). Five different experimental diets were prepared and administered for 28 days: (i) a control diet (C), a corn–soybean basal diet without antibiotics, ZnO, or a supplementation of growth promoters; (ii) a control diet with 400 mg/kg essential oil mixtures 1 (EOM1); (iii) a control diet supplemented with ZnO at 1600 mg/kg (Z); (iv) a diet incorporating the Z diet with the addition of essential oil mixtures 1 at 400 mg/kg (ZOM1); and (v) a diet incorporating the Z diet with the addition of essential oil mixtures 2 at 400 mg/kg (ZOM2). During day (d) 14–28 and d 1–28 of the experiment, the average daily gain (ADG) in piglets in the ZOM1 and ZOM2 groups were higher (p &lt; 0.05) compared to the C group. The diarrhea incidence of the Z, ZOM1, and ZOM2 groups were significantly decreased (p &lt; 0.05), and the piglets of the ZOM1 group exhibited the lowest diarrhea incidence throughout the trial period. Additionally, the apparent total tract digestibility (ATTD) of neutral detergent fiber (NDF), acid detergent fiber (ADF), ash, organic matter (OM), and ether extract (EE) were higher than those fed the Z diet, and higher levels of NDF, ADF, and crude protein (CP) were observed in groups other than those fed the ZOM1 diet (p &lt; 0.01). On d 14, the pigs fed EOM1 and ZOM2 diets showed a somewhat lower (p &lt; 0.1) immunoglobulin G (lgG) level in serum than those fed the C diet. Additionally, the IL-8 level in serum in the ZOM1 group tended to be higher than that in the other groups (p &lt; 0.1). The piglets fed the ZOM1 diet showed a tendency of lower (p = 0.05) acetate concentration in feces on d 14. Principal co-ordinates analysis (PCoA) showed significant differences (p &lt; 0.05) in the composition of fecal microbial communities among the groups. Dietary EOM1 significantly increased the number of fecal bacteroides (p &lt; 0.05) and tended to increase the number of Prevotella (p &lt; 0.1). Therefore, EOM1 combined with 1600 mg/kg ZnO tends to reduce diarrhea incidence, tends to improve the fecal microbial community structure and growth performance of weaned piglets, and has the potential to replace pharmacological dosages of ZnO.

Effects of the interaction between tank color and type of feed pellets on biological and physiological indicators in red hybrid tilapia (Oreochromis mossambicus × Oreochromis niloticus) juveniles reared in brackish water

AbstractThe present work aimed to investigate the impacts of tank color (transparent, light blue, and red), feed pellet types (floating and sinking), and their interaction on the performance and welfare of red hybrid tilapia juveniles with an initial average weight of 19.59 g for a 50 day trial period following a 3 × 2 factorial design. Fish were cultured randomly at a stoking rate of 10 juveniles/100‐L tank. Fish were fed 6 days per week at a rate of 4% biomass twice daily. Three replicates were performed for each measurement. A two‐way analysis of variance showed that using tanks of different colors (transparent, light blue, and red) has no impact on the growth, feed efficacy, survival rate, and blood composition (except for red blood cells, hematocrit, and triglycerides) of tilapia. Also, pellet types (floating and sinking) showed no significant alterations for the above variables except for glucose and hematocrit levels. Interestingly, the interaction between tank color and pellet type exhibited significant impacts on growth parameters, feed utilization, blood variables, and intestinal enzymes of red hybrid tilapia. Moreover, fish reared in transparent or light blue tanks and fed with floating diets performed the best for all evaluated parameters. Additionally, sinking pellets had better effects when combined with red (dark)‐colored tanks.

Venetoclax in Combination with Intermediate Doses of Cytarabine in Consolidation Phase for Acute Myeloid Leukemia Patients in First Complete Remission; Results of the Part 1 of the Phase 1/2 Multicentric Covenidac Study

For authors: Please: L Gastaud and P Peterlin: co-primary, H dombret et C Recher: co-last Background: The French ALFA-FILO AML intergroup launched the BIG-1 trial (EudraCT No.: 2014-000699-24) in 2015 to evaluate different intensive chemotherapy (ICT) strategies aiming at improving the survival of younger adults with acute myeloid leukemia (AML). All patients (pts) with previously untreated non-APL and non-CBF AML aged 18-60 years were eligible for this trial. The trial design included several randomization types. Results of the R1 and R2 randomizations, namely idarubicin vs daunorubicin for induction and IDAC vs HDAC for consolidation, will be reported at this meeting. In patients who achieved first complete remission (CR), randomizations R4 consisted of nested randomized Phase 2 or 1/2 studies evaluating the addition of new drugs to the IDAC/HDAC consolidation cycles. The protocol was designed to allow several sequential multicenter R4 evaluations of various new agents over the trial period. Venetoclax (VEN) has proved its efficacy when combined to azacitidine or low dose cytarabine in unfit AML pts (DiNardo et al. 2020; Wei et al. Blood 2020). Its role in fit patients treated with ICT is still under investigation. The COVENIDAC Phase 1/2 R4 sub-study is evaluating the safety and efficacy of VEN added to IDAC during the consolidation cycles of CR pts. We report herein the result of the Phase 1 part. Methods: The primary objective of this Phase 1 study was to determine the maximum tolerated dose (MTD) of VEN in combination with IDAC during the consolidation cycles, which will be the recommended dose for the Phase 2 (RP2D). Dose limiting toxicities (DLTs) were assessed during the first cycle of consolidation (C1) according to a 3+3 design. A maximum of 3 consolidation cycles was planned depending on the AML risk group. Hematological DLT was defined as no peripheral blood count recovery within 56 days from day 1 of the cycle. Non-hematological DLTs were defined as Grade ≥4 toxicities or Grade ≤3 toxicities which have not recovery by day 56 and deemed related to VEN per investigator opinion. VEN was started at dose level (DL) 1: 100 mg/d from day 1 to 8. In the absence of DLTs at DL1, 3 others DL were planned: 200 mg/d from day 1 to 8 (DL2); 400 mg/d from day 1 to 8 (DL3), and 400 mg/d from day 1 to 14 (DL4). IDAC was administrated at 1.5 gr/m² twice daily on day 1/3/5 for DL1, DL2 and DL3 pts, then on day 1/2/3 for DL4 pts after a protocol amendment. Main inclusion criteria were: pts in first CR following 1 or 2 courses of induction chemotherapy fit for further ICT; favorable and intermediate risk AML as defined by the protocol; ECOG PS ≤2; written informed consent. Measurable residual disease (MRD) was assessed by multiparametric flow cytometry (MFC) in all pts as well as NPM1-qPCR in NPM1-mutated pts. Results: Between 06/2021 and 04/2022, 15 pts from 9 centers were screened and enrolled. Pt characteristics were as follows: median age, 42 years (IQR, 30-49); 2 males/7 females; ECOG-PS, 0 in 10 pts and 1 in 5 pts; favorable/intermediate/adverse ELN-2017 risk, 9/2/4. Neutropenia and thrombocytopenia durations are shown in Table 1. Only 1 hematological DLT was observed at DL3 (platelet count of 96 giga/L at day 56 in a patient who was infected by Covid-19). Overall, there were very few non hematological AEs ( Table 2, no grade 4) and only 4 SAEs (1 related to IDAC/VEN during C1, 3 non-related). No non-hematological DLT was observed. No patient died during the DLT observation period, 1 experienced a septic shock (C2, DL2). One pt received only C1 (due to DLT), 7 received 2 cycles, and 7 received 3 cycles. Median time between initiation of subsequent consolidation cycles was 37.5 days (IQR, 35-41) for C1/C2 and 40 days (IQR, 35-43) for C2/C3. One pt had to stop VEN during C3. Six pts received an allogeneic HSCT (5 in CR1, 1 after salvage). With a median follow-up of 13.5 months, 3 pts relapsed and 2 died. MRD results will be presented. Conclusion: VEN/IDAC combination appears to be feasible and safe as consolidation therapy, with expected thrombocytopenia and neutropenia durations. These durations appeared even shorter at DL4, when IDAC was given on 3 consecutive days. VEN at 400 mg/d from day 1 to 14 combined with IDAC on day 1/2/3 was thus retained as RP2D for the randomized Phase 2 with RFS as primary endpoint. This phase 2 has already recruited 29 of the 200 pts planned.

RSK1 Is an Exploitable Dependency in Myeloid Malignancies

Myeloid malignancies harbor distinct molecular drivers but share convergence of oncogenic signaling pathways and propagation by ripe pro-inflammatory niches. To delineate these hallmarks across the spectrum of myeloid disease states, we established the largest comprehensive atlas of myeloproliferative neoplasms (MPN) and secondary acute myeloid leukemia (sAML) through RNA-sequencing and mass cytometry (CyTOF) of 370 primary samples encompassing CD34+ hematopoietic stem/progenitor cells and CD14+ monocytes, revealing aberrant of PI3K/AKT/mTOR signalling and NFκB-mediated hyper-inflammation. As a central mediator of these hyperactive signaling pathways, ribosomal S6 kinases (RSKs) represent potentially attractive novel therapeutic targets warranting further evaluation. Using both genetic approaches and a first-in-class oral RSK inhibitor, PMD-026, that is currently being evaluated in phase 1/1b clinical trials (NCT04115306) in metastatic and triple negative breast cancer, we found that RSK1 ( RPS6KA1) inhibition potently induced apoptosis and G2/M arrest in leukemia models in conjunction with suppression of PI3K/AKT/mTOR and NFκB signaling. Further NFκB cascade profiling following RSK1 perturbation revealed reduced phosphorylation of IKKα/β and p65/RELA and prevention of p65/RELA nuclear translocation. Using RNA-seq, ATAC-seq and H3K27ac CUT&amp;Tag, we found that PMD-026 treatment altered chromatin accessibility and inhibited NFKB1, TNF, and cell cycle regulators CCNA1/2 and CDK1/2. In cytokine CyTOF, PMD-026 nearly abrogated all induction of inflammatory cytokines including TNF, IL-6, IL-8, CCL3, and CCL4 in primary MPN monocytes to levels substantially below basal conditions. We further extended our findings to de novo AML harboring FLT3 internal tandem duplication ( FLT3-ITD), where FLT3-ITD patients exhibited elevated RPS6KA1 expression and those who developed resistance to gilteritinib demonstrated progressively increased RPS6KA1 expression. FLT3-ITD cells exhibited preferentially sensitivity to RSK1 inhibition, where we uncovered bi-directional regulation. Through cycloheximide, MG-132, and ubiquitination assays, we found that RSK1 regulates FLT3-ITD activity and protein stability through deubiqutinase USP1, and where either RPS6KA1 or USP1 inhibition resulted in concomitant downregulation of FLT3 protein and cell lethality. Multivariate analysis of the TCGA and BeatAML cohorts (n= 568 patients) revealed high median USP1 or RPS6KA1 expression to be significantly associated with poor survival, thus defining a RSK1-USP1-FLT3 axis with prognostic relevance. Across in vivo models, PMD-026 ameliorated MPN disease features driven by MPL W515L including leukocytosis, splenomegaly, and bone marrow fibrosis, while prolonging survival, in conjunction with suppression of inflammatory cytokines including TNF, IL-6 and IL-1b. We then evaluated PMD-026 across five patient-derived xenograft (PDX) models spanning the spectrum of myeloid malignancies including myelofibrosis (MF), sAML, and chronic myelomonocytic leukemia (CMML) encompassing various driver and multiple high-risk mutations. Treatment in MF PDX mice decelerated disease progression, extended survival, and reduced splenomegaly, while in CMML/sAML PDXs, PMD-026 led to a 67 to 96 percent reduction in human CD45+ cells engraftment. Finally, PMD-026 treatment in both mice xenografted with MV4-11 cells and syngeneic Flt3ITDTet2KO mice significantly reduced leukemic cell engraftment and prolonged survival. These data indicate potent efficacy of RSK inhibition across diverse models of chronic and acute myeloid malignancies. Lastly, we investigated the impact of PMD-026 on hematological parameters from 41 breast cancer patients enrolled in the phase 1/1b clinical trial. Overall, there was no sustained suppressive effect on hematological parameters and there were no hematological PMD-026-related toxicities meeting criteria for dose modification during the trial period. These clinical data demonstrate that PMD-026 did not cause myelosuppression. Our findings uncover a novel therapeutic avenue for a conserved RSK1 dependency across chronic and acute myeloid neoplasms. The potent and consistent disease-ameliorating effects across numerous leukemia mouse models demonstrates promise for repurposing PMD-026 for the treatment of myeloid malignancies.

Artistic Play and Laughter as a Way of Living in Art

The article deals with the duality of a rational, sane worldview and an oppositional-irrational, namely a laughable and theatrical way of reinterpreting reality and life in this "other reality". It is emphasized that the instinct of play, theatricality, and a sense of humor from the earliest times (prehistoric eras) was and still is a manifestation of individual freedom. The instinct of play as a manifestation of cultural self-awareness is represented as a sign of psychological and mental health. Options for rethinking rational life within the framework of the "laughing instinct" are considered in the review of creative approaches to reality by Serhiy Parajanov (his collages), in the stage techniques of Bohdan Stupka. For the first time in Ukrainian art history, the "laughter" of Lucien Dulfan — an artist from Odesa, and since the 1980s — a New Yorker, has been considered. The Odessa "laughter space" was also traced in the works of Serhiy Bozhek and Igor Gusev (their anti-war work of 2022). The painting of Vladyslav Shereshevsky is visualized from the point of view of the "carnival double". Negativist, cynical manifestations of laughter and play in the works of individual representatives of Ukrainian contemporary art were also noted. The article analyzes the positive role of laughter in the works of Ukrainian artists of 2022–2023 in their protest against Putinism. The prognostic value of artistic gestures is illustrated on the example of Serhiy Parajanov's work, which, breaking the law of continuity and normality in art, in creative outbursts (moments of bifurcation), shake the old system of artistic thinking, offering novelty. Laughter in this situation is a guide to prognostication. The article shows how the creative theatricalization of the worldview, the transformation of the tragic into the comic with a joke, in a game and a laugh, is able to save a person not only from lame pragmatism in everyday life, but also from a tragic sense of well-being during periods of severe trials, in particular, when confronting the barbarism of war.

Analyzing The Efficacy of &lt;em&gt;Salvinia molesta&lt;/em&gt; and &lt;em&gt;Pistia stratiotes&lt;/em&gt; as Phytoremediation Agent for Heavy Metals

To rejuvenate our declining ecosystems, it is imperative to promptly face the issue of heavy metal contamination, which serves as the underlying cause for pollution globally. Phytoremediation, which is the ability of certain plants to accumulate, break down, or neutralize pollutants in water, soil, or air, offers a promising solution. The current investigation aimed to assess the efficacy of Salvinia molesta and Pistia stratiotes in removing heavy metals from apparel industrial wastewater. In a controlled indoor environment, the wastewater underwent treatment using these plants, while control tanks of the same size without any plants were maintained for comparison. This setup included three replicates for each treatment. Over 18 days, samples of the wastewater were collected and analyzed for the presence of Cadmium (Cd), Copper (Cu), and Zinc (Zn) using an Atomic Absorption Spectrophotometer (AAS) every three days. An initial analysis of the untreated wastewater was conducted. Statistical analysis employed one-way ANOVA to compare the average concentrations in the effluent and the removal percentages across various treatment conditions. Pistia stratiotes exhibited a higher Cd reduction rate (29.97%) compared to Salvinia molesta (18.13%). Tanks containing Salvinia molesta showed a more substantial Cu removal rate (52.47%), while Pistia stratiotes demonstrated a lower Cu reduction (42.37%). As for Zinc (Zn), it decreased by 22.89% and 17.87% in tanks where Salvinia molesta and Pistia stratiotes were used, respectively. This study, conducted over an 18-day trial period, underscores the effectiveness of both plant types in removing Cd, Cu, and Zn from the wastewater. The preferential absorption was observed for Cu over the other two metals. For Salvinia molesta, the removal efficiency followed the sequence: Cu&gt;Zn&gt;Cd, whereas for Pistia stratiotes, it was Cu&gt;Cd&gt;Zn. These findings demonstrate that both plant species can thrive while accumulating these heavy metals in apparel industrial wastewater.