Model For Repeated Measures Research Articles

Determination of the mean duration of recent infection and false recency rate for the HIV triplex multiplex bead assay.

We developed the HIV Triplex multiplex bead assay to identify and serotype HIV infection with high sensitivity and specificity; and distinguish recent from long-term HIV-1 infections. It can facilitate accurate incidence estimation, while reducing the number of tests and blood collected, which is highly desirable for use in future studies and surveys. Using previously collected, treatment-naive longitudinal seroconversion HIV-1 positive panels and specimens from individuals infected for >12 months, we determined the assay's mean duration of recent infection (MDRI) and false-recency rate (FRR) respectively, at various mean fluorescent intensity (MFI) cutoffs. We tested seroconversion specimens (N = 814) from 142 individuals infected with HIV-1 subtypes B, C, or AE, and 1341 cross-sectional specimens from individuals infected >12 months. The MFI cutoffs of 1000 to 2000 were evaluated for recency classification, including an MFI of 1250 corresponding to the limiting antigen avidity enzyme immunoassay (LAg-EIA) cutoff of 1.5 normalized optical density for MDRI and FRR. We used four statistical methods: Methods 1 and 2 used the empirically balanced observation time approach. Method 2 MFI values were raised to power = 1.33, based on a repeated measures model to linearize the relationship between MFI and time points, whereas Method 1 was not linearized. Methods 3 and 4 employed quadratic and linear interpolations for each seroconversion panel. FRR was calculated by dividing the number of specimens misclassified as recent by the total number of specimens tested. MDRI values ranged from 135-146 days at MFI = 1000 to 229-279 days at MFI = 2000 by the 4 methods. FRR varied from 0.15%-1.27% with increasing MFI cutoff. At MFI = 1250, the average MDRI of 4 methods was 169 days and ranged from 159-183 with overlapping 95% CIs and FRR = 0.52%. The HIV Triplex assay demonstrates a longer dynamic range compared to current HIV recency assays with a low FRR for cutoffs examined. With a longer dynamic range and low FRR, the MDRI for recent infection can be extended as appropriate to detect more recent infections, increasing the value of incidence assays benefiting public health surveillance and future surveys.

Atrasentan in Patients with IgA Nephropathy.

Patients with IgA nephropathy and severe proteinuria have a high lifetime risk of kidney failure. The efficacy and safety of the selective endothelin type A receptor antagonist atrasentan in reducing proteinuria in patients with IgA nephropathy are incompletely understood. We are conducting a phase 3, multinational, double-blind, randomized, controlled trial involving adults with biopsy-proven IgA nephropathy, a total urinary protein excretion of at least 1 g per day, and an estimated glomerular filtration rate of at least 30 ml per minute per 1.73 m2 of body-surface area. Patients were randomly assigned to receive atrasentan (0.75 mg per day) or matched placebo for 132 weeks. The primary outcome, assessed at a prespecified interim analysis of data from the first 270 patients in the main stratum, was the change in the 24-hour urinary protein-to-creatinine ratio from baseline to week 36; the change was estimated with the use of a repeated-measures model. (An exploratory stratum of patients who were receiving a sodium-glucose cotransporter 2 inhibitor were included in a separate analysis.) Safety analyses were based on adverse events across the entire main stratum. A total of 340 patients were recruited into the main stratum. Among the first 270 patients in the main stratum (135 per trial group) who completed the week 36 visit, the geometric mean percentage change in the urinary protein-to-creatinine ratio relative to baseline was significantly greater with atrasentan (-38.1%) than with placebo (-3.1%), with a geometric mean between-group difference of -36.1 percentage points (95% confidence interval, -44.6 to -26.4; P<0.001). The percentage of patients with adverse events did not differ substantially between the two groups. Fluid retention was reported by 19 of 169 patients (11.2%) in the atrasentan group and in 14 of 170 (8.2%) in the placebo group but did not lead to discontinuation of the trial regimen. No apparent cases of cardiac failure or severe edema occurred. In this prespecified interim analysis, atrasentan resulted in a significant and clinically meaningful reduction in proteinuria as compared with placebo in patients with IgA nephropathy. (Funded by Novartis; ALIGN ClinicalTrials.gov number, NCT04573478.).

Citrus tamurana Hort. ex Tanaka (Hyuganatsu orange)-derived arabinogalactan suppresses bone turnover in postmenopausal women: A randomized placebo-controlled study.

To evaluate Hyuganatsu oranges (Citrus tamurana Hort. Ex Tanaka) derived arabinogalactan for bone turnover, we performed a randomized placebo-controlled trial. Sixty-three postmenopausal women were age-stratified and randomly assigned to receive arabinogalactan-rich hyuganatsu juice (study group) or a placebo drink (control group) for 90 days. We measured blood tartrate-resistant acid phosphatase 5b (TRACP5b), type I procollagen N-terminal propeptide (P1NP), and other bone turnover biomarker levels at baseline, days 45 and 90 (T90) of the intervention, and day 30 of recovery. Cumulative effects were compared between groups using repeated-measures linear mixed model analysis. The primary endpoint was the difference between the pre- and post-intervention TRACP5b and P1NP levels. Using repeated measures linear mixed model analysis, the study group had significantly lower TRACP5b and P1NP levels at day 90 than the control group (mean [95% confidence interval]; TRACP5b: 310.0 [269.2-350.9] vs. 386.4 [341.2-431.6] mU/dL; P1NP: 53.7 [48.6-58.7] vs. 70.3 [64.1-76.4] ng/mL), whereas other biomarker levels showed no change. Arabinogalactan-rich Hyuganatsu juice suppressed bone mineral turnover and potentially improved ovarian hormone deficiency-induced osteoporosis in postmenopausal women.

Impact of an mHealth intervention on parents' emotional health and on the neurodevelopment of high-risk infants.

We assess the prenatal and postnatal effect of the High-Risk Pregnancy and Baby Parenting programme, which is complemented with two mHealth (app-based) resources. The GLM Repeated Measures Model technique was used to explore differences in the emotional health of the participants and in their infants' neurodevelopment, comparing programme versus usual care groups, composed of 150 and 195 participants, respectively. The mothers presented lower levels of depression (mean difference 1.74, p = 0.04, 95% CI 0.07, 3.40) and higher levels of resilience (mean difference 4.09, p = 0.004, 95% CI 1.40, 6.78). For the fathers, positive effects on resilience were recorded (p < 0.001). A positive treatment effect was perceived in the infants' cognitive (p = 0.014), language (p < 0.001) and motor (p = 0.006) development. These findings suggest application of the programme can benefit maternal emotional health and infant neurodevelopment. M-Health technology could make this programme more accessible.

A longitudinal path model examining the transactional nature of parenting and child externalizing behaviors in a large, sociodemographically diverse sample.

Children's externalizing behaviors are associated with impairments across the lifespan. Developmental psychopathology theories propose transactional (bidirectional) associations between child externalizing behaviors and parenting during childhood and adolescence. Yet, these foundational relations in early childhood are not well-studied. Utilizing a large, mixed-sex sample, we examined the reciprocal nature of parenting and child externalizing behaviors across early childhood using robust repeated-measures models. Repeated measures data were drawn from a socioeconomically diverse, longitudinal pregnancy cohort of 1287 (64% Black, 31% White) mother-child dyads at four time points (ages one to six). Three variables were included in cross-lagged panel models: observed parenting quality, child externalizing symptoms, and a maternal risk composite. In covariate-adjusted models, higher parenting quality at Wave 1 predicted lower child externalizing symptoms at Wave 2. Higher externalizing symptoms at Wave 1 and Wave 2 predicted lower parenting quality at Wave 2 and Wave 3, respectively. Maternal risk and parenting quality were not significantly associated. Findings showed both parent-driven and child-driven effects across early childhood that did not vary by child sex. The transactional nature of the parent-child relationship begins in infancy, underscoring the importance of early screening and provision of supports for families to minimize and prevent the development of serious psychopathology.

Tirzepatide and blood pressure reduction: stratified analyses of the SURMOUNT-1 randomised controlled trial

BackgroundTreating obesity may be a pathway to prevent and control hypertension. In the SURMOUNT-1 trial in people with obesity or overweight with weight-related complications, 72-week tirzepatide treatment led to clinically...

The effects of treatment, clinical and demographic factors on recovery of orientation after ECT: A care network study

BackgroundTime to reorientation after electroconvulsive therapy (ECT) has been shown to predict retrograde amnesia and is a useful measure for monitoring patients over the acute treatment course. This study investigated the effects of treatment, clinical and demographic factors on the recovery of orientation after ECT. MethodsData from 555 ECT patients across two different clinical CARE Network sites were analysed. The main outcome variable was recovery of orientation on the 10-Item Orientation Questionnaire assessed after every ECT treatment. A linear mixed-effects repeated measures model was used to predict the recovery of orientation across the ECT course based on multiple factors, including age, gender, electrode montage, ECT number and frequency, diagnosis, and baseline cognitive impairment. ResultsType of ECT demonstrated a significant effect (F(2, 2341) = 48.414, p = 0.000): individuals who received right unilateral (RUL) ultrabrief ECT or bifrontal ECT had higher orientation scores compared to those who received RUL brief pulse ECT. Older age groups and female patients had lower orientation scores. Baseline global cognitive functioning significantly influenced orientation scores (F(3, 2339) = 43.597, p = 0.000), with individuals with no or mild cognitive impairment exhibiting higher scores. LimitationsThe study involved a retrospective analysis of de-identified data, which may have introduced inherent biases with missing data. ConclusionsThis large-scale retrospective, real-world study showed that recovery of orientation after ECT was most affected by ECT type, though age, gender, and baseline level cognitive impairment also affected outcomes. These findings can inform the interpretation of post ECT orientation scores, facilitating its monitoring and optimisation of patient outcomes.

206 Effects of breed type and days on trial on feeding behavior in growing goats fed a total mixed diets using GrowSafe feeding technology

Abstract The objective of this study was to evaluate the effects of breed and days on trial (DOT) on feeding behavior traits in two breeds of growing goats. Nineteen female goats [n = 10 Alpine; n = 9 Spanish, with average initial ages of 360 d and 352 d, and body weight (BW) of 38.8 ± 2.8 kg and 35.5 ± 3.1 kg, respectively], were randomly assigned within the breed to one of two non-adjacent pens (5 goats/pen), each equipped with GrowSafe feed bunks. A pelletized total mixed ration (TMR) was fed twice per day and goats had ad libitum access to feed, water, and mineral block throughout the 84-d trial. Feeding behavior traits, including feed intake, bunk visit frequency (BVF), head-down duration (HDD), and dry matter intake (DMI) were collected daily using the GrowSafe feeding system. A 14-d interval was used to derive feed behavior traits of individual goats at 42, 56, 70, and 84 DOT. Data were analyzed using a repeated-measures model with a fixed effect of breed, DOT as a repeated measure, and breed x DOT interaction with pen as a random effect. Alpine goats had greater (P &amp;lt; 0.05) initial and final BW (37.6 kg and 51.7 kg, respectively) than Spanish goats (34.7 kg and 46.5 kg, respectively) although DMI (P = 0.10; 1.73 ± 0.31 and 1.39 ± 0.18 kg/d) did not differ. There was not a significant difference (P &amp;gt; 0.05) between breeds for frequency of bunk visits (21.1 vs. 18.6) and bunk duration (P &amp;gt; 0.05). Similarly, the effect of breed on DMI (27.1g/min vs. 22.8 g/min) was non-significant (P &amp;gt; 0.05). Furthermore, breed did not significantly (P &amp;gt; 0.05) affect HDD (31.3 min/d vs 31.9 min/d). However, there was a significant interaction (P &amp;lt; 0.05) between breed and DOT for HDD. In addition, significant differences (P &amp;lt; 0.05) were observed due to the length of DOT for BVD, bunk visit duration, HDD, and eating rate (g/min). Our results suggest that Spanish goats tended to visit feed bunks more frequently per day and tended to consume less feed per visit than their counterpart Alpine goats, and the feeding behaviors of goats change with age. However, further research is warranted to determine changes in the feeding behavior of goats in different production cycles.

Associations Between Flavonoid Intake and Subclinical Atherosclerosis: The MESA.

Flavonoids may play a role in mitigating atherosclerotic cardiovascular diseases, with evidence suggesting effects may differ between vascular beds. Studies examining associations with subclinical markers of atherosclerosis between subpopulations with different underlying risks of atherosclerosis are lacking. Among 5599 participants from the MESA (Multi-Ethnic Study of Atherosclerosis), associations between dietary flavonoid intakes (estimated from a food frequency questionnaire) and subclinical measures of atherosclerosis (ankle-brachial index, carotid plaques and intima-media thickness, and coronary artery calcification) were examined using repeated measures models. Exposures and outcomes were measured at exam 1 (2000-2002) and exam 5 (2010-2011). Stratified analyses and interaction terms were used to explore effect modification by time, sex, race/ethnicity, and smoking status. In the analytic population, at baseline, ≈46% were males with a median age of 62 (interquartile range, 53-70) years and total flavonoid intakes of 182 (interquartile range, 98-308) mg/d. After multivariable adjustments, participants with the highest (quartile 4) versus lowest (quartile 1) total flavonoid intakes had 26% lower odds of having an ankle-brachial index <1 (odds ratio, 0.74 [95% CI, 0.60-0.92]) and 18% lower odds of having a carotid plaque (odds ratio, 0.82 [95% CI, 0.69-0.99]), averaged over exams 1 and 5. Moderate (quartile 3) to high (quartile 4) intakes of flavonols, flavanol monomers, and anthocyanins were associated with 19% to 34% lower odds of having an ankle-brachial index <1 and 18% to 20% lower odds of having carotid plaque. Participants with the highest intakes of anthocyanins (quartile 4) at baseline had a marginally slower rate of carotid plaque progression than those with moderate intakes (quartiles 2 and 3). There were no significant associations with intima-media thickness or coronary artery calcification. Observed associations did not differ by sex, race/ethnicity, or smoking status. In this multi-ethnic population, higher dietary flavonoid intakes were associated with lower odds of peripheral and carotid artery atherosclerosis. Increasing intakes of healthy, flavonoid-rich foods may protect against atherosclerosis in the peripheral and carotid arteries.

Mirtazapine to alleviate severe breathlessness in patients with COPD or interstitial lung diseases (BETTER-B): an international, multicentre, double-blind, randomised, placebo-controlled, phase 3 mixed-method trial

Breathlessness frequently becomes severe among people with respiratory disease. Mirtazapine, a widely used antidepressant, has shown promise in the modulation of respiratory sensation and the response to it, as well as reducing feelings of panic, which often accompanies breathlessness. We aimed to determine the effectiveness of mirtazapine to alleviate severe persisting breathlessness. This international, multicentre, phase 3, parallel-group, double-blind, randomised, placebo-controlled trial across 16 centres in seven countries (Australia, Germany, Ireland, Italy, New Zealand, Poland, and the UK), recruited adults with chronic obstructive pulmonary disease (COPD), interstitial lung diseases, or both, and grade 3 or 4 of the modified Medical Research Council breathlessness scale. Consenting participants were randomly assigned (1:1) to receive oral mirtazapine or matching placebo for 56 days. Randomisation was by minimisation. The initial mirtazapine dose was 15 mg, escalating to a maximum of 45 mg per day, tapered at treatment end. Participants, caregivers, assessors, and investigators were masked to group assignment. The primary outcome was worst breathlessness in the preceding 24 h measured on a 0-10 numerical rating scale (NRS), at 56 days post-treatment start, with follow-up to 180 days. The primary analysis was performed in the modified intention-to-treat population using multivariable multi-level repeated measures model. This trial was registered with ISRCTN (ISRCTN10487976 and ISRCTN15751764 [Australia and New Zealand]) and EudraCT (2019-002001-21) and is complete. Between Feb 4, 2021 and March 28, 2023, we enrolled 225 eligible participants (148 men and 77 women, 113 to the mirtazapine group and 112 to the placebo group). The median age was 74 years (IQR 67-78). No evidence of a difference was found in worst breathlessness at day 56 between mirtazapine and placebo (difference in adjusted mean NRS score was 0·105 [95% CI -0·407 to 0·618]; p=0·69). Although the study was underpowered, the primary endpoint effect did not reach the pre-specified treatment effect of 0·55 for worst breathlessness score reduction that the study was powered to detect for the primary analysis. There were 215 adverse reactions in 72 (64%) of 113 participants in the mirtazapine group versus 116 in 44 (40%) of 110 participants in the placebo group; 11 serious adverse events in six (5%) participants in the mirtazapine group versus eight in seven (6%) participants in the placebo group; and one (1%) suspected unexpected serious adverse reaction in the mirtazapine group. At day 56, there were three deaths in the mirtazapine group and two deaths in the placebo group. At day 180, there were seven deaths in the mirtazapine group and 11 deaths in the placebo group. Our findings suggested that mirtazapine of doses 15 to 45 mg daily over 56 days does not improve severe breathlessness among patients with COPD or interstitial lung diseases and might cause adverse reactions. Based on these findings, we do not recommend mirtazapine as a treatment to alleviate severe breathlessness. EU Horizon 2020 (grant agreement No. 825319); Cicely Saunders International Breathlessness Programme; National Institute for Health and Care Research Applied Research Collaboration South London; Australian National Health and Medical Research Council-EU (application ID: APP1170731).

Ultraprocessed food intake and body mass index change among youths: a prospective cohort study

BackgroundSuboptimal diets may promote undesired weight gain in youths, with high ultraprocessed food (UPF) intake becoming a significant concern in the United States. ObjectivesWe evaluated the association between UPF intake and body mass index [BMI (in kg/m2)] change in large United States youth cohorts. MethodsParticipants included children and adolescents (7–17 y) from the Growing Up Today Study (GUTS1 and GUTS2) who completed baseline and ≥1 follow-up diet and anthropometrics assessment (GUTS1 1996–2001: N = 15,797; GUTS2 2004–2011: N = 9720). Follow-up years were based on diet assessment availability. UPFs were categorized using the Nova system, with intakes evaluated as the cumulative mean percent energy from UPFs and subgroups. BMI was assessed using self-reported body weight/height. Changes in BMI annually and over 2, 4–5, and 7 y in association with UPF intake were examined using multivariable repeated-measure linear mixed models. ResultsAt baseline, the mean percentage of energy from UPFs was 49.9% in GUTS1 and 49.5% in GUTS2 participants; mean BMI was 18.7 and 19.8, respectively. After multivariable adjustments for sociodemographic and lifestyle factors, each 10% increment in UPF intake was associated with a 0.01 (95% confidence interval: 0.003, 0.03) increase annually and a 0.07 (0.01, 0.13) increase over 5 y in GUTS1 participants. In GUTS2, increases were 0.02 (0.003, 0.04) annually and 0.09 (0.01, 0.18) over 4 y. Among GUTS1, statistically significant annual BMI increases of 0.02–0.07 were associated with elevated intake of ultraprocessed breakfast cereals, savory snacks, and ready-to-eat/heat foods, especially pizza, burgers, and sandwiches. No association was found between UPF intake and overweight/obesity risk. ConclusionsA higher UPF intake was associated with a modest yet significant increase in BMI in large prospective cohorts of United States youths, calling for public health efforts to promote healthful food intake among youths to prevent excessive weight gain.

Comparison of IL-6, IL-10, and TNFα levels between PLWHIV with and without Kaposi Sarcoma and healthy controls.

Kaposi sarcoma (KS) is an angioproliferative disease caused by human herpesvirus 8 (HHV-8) and is mediated by cytokines in an immunodeficient environment. This study aimed to compare IL-6, IL-10, and TNFα levels among AIDS patients with disseminated KS (DKS), treatment naïve patients living with HIV (PLWHIV) without DKS, and healthy controls. Secondary outcomes were to compare cytokines levels in patients with DKS and unfavorable outcomes, as well as an analysis of the behavior of cytokines over time. This cohort study was performed at two centers in Mexico City. Three groups were included. Group 1: HIV+ treatment naïve with DKS, Group 2: HIV+ treatment naïve without KS, and Group 3: HIV negative, healthy controls. Plasmatic IL-6, IL-10, and TNFα levels were measured at baseline and over time in Groups 1 and 2. Seventy-six patients were included: 39 (52%) in Group 1, 17 (22%) in Group 2, and 20 (26%) in Group 3. The median baseline IL-6, IL-10, and TNFα levels were significantly higher in group 1. In group 1, baseline IL-6 was higher in patients who died than in survivors (14.4 vs 5.8 pg/mL p=0.048). Patients with severe immune reconstitution inflammatory syndrome due to KS (S-IRIS-KS) had higher IL-6 values than those without it (14.4 vs 5.8 pg/mL p=0.004). In the repeated-measures model in group 1, IL-10 levels were higher in patients who died (p<0.001) and developed IRIS-KS (p=0.01). IL-6, IL-10, and TNF α levels were markedly higher in patients with DKS. IL-6 and IL-10 levels were higher in patients with unfavorable outcomes.

Quality of life in cemiplimab-treated patients with locally advanced basal cell carcinoma in a Phase IIclinical trial.

Aim: To evaluate health-related quality of life (HRQoL) in cemiplimab-treated patients with locally advanced basal cell carcinoma (laBCC). Materials & methods: Eighty-four patients withlaBCC received cemiplimab 350mg every 3weeks (up to 9 cycles). HRQoL was assessed using the European Organization for Research and Treatment of Cancer Quality of Life Core 30 (QLQ-C30) and Skindex-16 questionnaires at baseline and each cycle. Mixed-effects repeated-measures models evaluated change from baseline across cycles. Results: Clinically meaningful improvement or maintenance was reported by 62-90% of patients on QLQ-C30 scales and by approximately80% on Skindex-16 scales at Cycle 2, with consistent results at Cycle 9 except fatigue. Conclusion: Most cemiplimab-treated patients with laBCC reported improvement or maintenance of HRQoL with low symptom burden except fatigue.Clinical Trial Registration: ClinicalTrials.gov identifier NCT03132636, registered 28April 2017.

Anti-inflammatory therapy with nebulized dornase alfa for severe COVID-19 pneumonia: a randomized unblinded trial.

Prinflammatory extracellular chromatin from neutrophil extracellular traps (NETs) and other cellular sources is found in COVID-19 patients and may promote pathology. We determined whether pulmonary administration of the endonuclease dornase alfa reduced systemic inflammation by clearing extracellular chromatin. Eligible patients were randomized (3:1) to the best available care including dexamethasone (R-BAC) or to BAC with twice-daily nebulized dornase alfa (R-BAC + DA) for seven days or until discharge. A 2:1 ratio of matched contemporary controls (CC-BAC) provided additional comparators. The primary endpoint was the improvement in C-reactive protein (CRP) over time, analyzed using a repeated-measures mixed model, adjusted for baseline factors. We recruited 39 evaluable participants: 30 randomized to dornase alfa (R-BAC +DA), 9 randomized to BAC (R-BAC), and included 60 CC-BAC participants. Dornase alfa was well tolerated and reduced CRP by 33% compared to the combined BAC groups (T-BAC). Least squares (LS) mean post-dexamethasone CRP fell from 101.9 mg/L to 23.23 mg/L in R-BAC +DA participants versus a 99.5 mg/L to 34.82 mg/L reduction in the T-BAC group at 7 days; p=0.01. The anti-inflammatory effect of dornase alfa was further confirmed with subgroup and sensitivity analyses on randomised participants only, mitigating potential biases associated with the use of CC-BAC participants. Dornase alfa increased live discharge rates by 63% (HR 1.63, 95% CI 1.01-2.61, p=0.03), increased lymphocyte counts (LS mean: 1.08 vs 0.87, p=0.02) and reduced circulating cf-DNA and the coagulopathy marker D-dimer (LS mean: 570.78 vs 1656.96 μg/mL, p=0.004). Dornase alfa reduces pathogenic inflammation in COVID-19 pneumonia, demonstrating the benefit of cost-effective therapies that target extracellular chromatin. LifeArc, Breathing Matters, The Francis Crick Institute (CRUK, Medical Research Council, Wellcome Trust). NCT04359654.

Anti-inflammatory therapy with nebulized dornase alfa for severe COVID-19 pneumonia: a randomized unblinded trial

Background:Prinflammatory extracellular chromatin from neutrophil extracellular traps (NETs) and other cellular sources is found in COVID-19 patients and may promote pathology. We determined whether pulmonary administration of the endonuclease dornase alfa reduced systemic inflammation by clearing extracellular chromatin.Methods:Eligible patients were randomized (3:1) to the best available care including dexamethasone (R-BAC) or to BAC with twice-daily nebulized dornase alfa (R-BAC + DA) for seven days or until discharge. A 2:1 ratio of matched contemporary controls (CC-BAC) provided additional comparators. The primary endpoint was the improvement in C-reactive protein (CRP) over time, analyzed using a repeated-measures mixed model, adjusted for baseline factors.Results:We recruited 39 evaluable participants: 30 randomized to dornase alfa (R-BAC +DA), 9 randomized to BAC (R-BAC), and included 60 CC-BAC participants. Dornase alfa was well tolerated and reduced CRP by 33% compared to the combined BAC groups (T-BAC). Least squares (LS) mean post-dexamethasone CRP fell from 101.9 mg/L to 23.23 mg/L in R-BAC +DA participants versus a 99.5 mg/L to 34.82 mg/L reduction in the T-BAC group at 7 days; p=0.01. The anti-inflammatory effect of dornase alfa was further confirmed with subgroup and sensitivity analyses on randomised participants only, mitigating potential biases associated with the use of CC-BAC participants. Dornase alfa increased live discharge rates by 63% (HR 1.63, 95% CI 1.01–2.61, p=0.03), increased lymphocyte counts (LS mean: 1.08 vs 0.87, p=0.02) and reduced circulating cf-DNA and the coagulopathy marker D-dimer (LS mean: 570.78 vs 1656.96 μg/mL, p=0.004).Conclusions:Dornase alfa reduces pathogenic inflammation in COVID-19 pneumonia, demonstrating the benefit of cost-effective therapies that target extracellular chromatin.Funding:LifeArc, Breathing Matters, The Francis Crick Institute (CRUK, Medical Research Council, Wellcome Trust).Clinical trial number:NCT04359654.

Estimation Methods for Three-Way Repeated Measurements Model

In this paper, we study two estimation methods for a three-way repeated measurements model. We estimated the variance components by using the maximum likelihood method and penalized likelihood method. We determine the moments of each estimator, also we define the likelihood ratio test statistic. We look at the various factors that contribute to accuracy, such as sample size, and biased estimation.

Outpatient interdisciplinary multimodal pain treatment programme for patients with chronic musculoskeletal pain: a longitudinal cohort study

Purpose To describe the outcomes of an interdisciplinary multimodal pain treatment (IMPT) for chronic musculoskeletal pain (CMP) patients up until 12 months post-treatment. Materials and Methods Data were gathered during routine clinical practice during a 3-year period (2019–2021) at six Dutch rehabilitation centres. Assessments included patient-reported outcome measures for multiple domains including disability, pain and fatigue. Longitudinal data were analysed using repeated-measures models and by quantifying responder rates. Results Included were 2309 patients with a mean age of 43.7 (SD 12.9) years, of which 73% female. All outcomes showed significant improvements at each timepoint. At discharge, large effect sizes were found for disability, average and worst pain, fatigue and health-related quality of life. Improvements were largely sustained at 12-months. Relatively large proportions of patients had clinically relevant improvements after treatment (pain-related disability: 60%; average pain: 52%; worst pain: 37.4%; work capacity: 50%; concentration: 50%; fatigue: 46%). Patients who received a treatment extension showed further improvements for all outcome measures, except average pain. Conclusions At group level, all outcomes significantly improved with mainly large effect sizes. The results were mostly sustained. The proportion of patients showing clinically relevant improvements tends to be larger than previously reported for mixed CMP patients.

Supporting self-management of low back pain with an internet intervention with and without telephone support in primary care (SupportBack 2): a randomised controlled trial of clinical and cost-effectiveness

Low back pain is prevalent and a leading cause of disability. We aimed to determine the clinical and cost-effectiveness of an accessible, scalable internet intervention for supporting behavioural self-management (SupportBack). Participants in UK primary care with low back pain without serious spinal pathology were randomly assigned 1:1:1 using computer algorithms stratified by disability level and telephone-support centre to usual care, usual care and SupportBack, or usual care and SupportBack with physiotherapist telephone-support (three brief calls). The primary outcome was low back pain-related disability (Roland Morris Disability Questionnaire [RMDQ] score) at 6 weeks, 3 months, 6 months, and 12 months using a repeated measures model, analysed by intention to treat using 97·5% CIs. A parallel economic evaluation from a health services perspective was used to estimate cost-effectiveness. People with lived experience of low back pain were involved in this trial from the outset. This completed trial was registered with ISRCTN, ISRCTN14736486. Between Nov 29, 2018, and Jan 12, 2021, 825 participants were randomly assigned (274 to usual care, 275 to SupportBack only, 276 to SupportBack with telephone-support). Participants had a mean age of 54 (SD 15), 479 (58%) of 821 were women and 342 (42%) were men, and 591 (92%) of 641 were White. Follow-up rates were 687 (83%) at 6 weeks, 598 (73%) at 3 months, 589 (72%) at 6 months, and 652 (79%) at 12 months. For the primary analysis, 736 participants were analysed (249 usual care, 245 SupportBack, and 242 SupportBack with telephone support). At a significance level of 0·025, there was no difference in RMDQ over 12 months with SupportBack versus usual care (adjusted mean difference -0·5 [97·5% CI -1·2 to 0·2]; p=0·085) or SupportBack with telephone-support versus usual care (-0·6 [-1·2 to 0·1]; p=0·048). There were no treatment-related serious adverse events. The economic evaluation showed that the SupportBack group dominated usual care, being both more effective and less costly. Both interventions were likely to be cost-effective at a threshold of £20 000 per quality adjusted life year compared with usual care. The SupportBack internet interventions did not significantly reduce low back pain-related disability over 12 months compared with usual care. They were likely to be cost-effective and safe. Clinical effectiveness, cost-effectiveness, and safety should be considered together when determining whether to apply these interventions in clinical practice. National Institute for Health and Care Research Health Technology Assessment (16/111/78).

Prolonged intermittent theta burst stimulation targeting the left prefrontal cortex and cerebellum does not affect executive functions in healthy individuals

Repetitive transcranial magnetic stimulation (rTMS) for alleviating negative symptoms and cognitive dysfunction in schizophrenia commonly targets the left dorsolateral prefrontal cortex (LDLPFC). However, the therapeutic effectiveness of rTMS at this site remains inconclusive and increasingly, studies are focusing on cerebellar rTMS. Recently, prolonged intermittent theta-burst stimulation (iTBS) has emerged as a rapid-acting form of rTMS with promising clinical benefits. This study explored the cognitive and neurophysiological effects of prolonged iTBS administered to the LDLPFC and cerebellum in a healthy cohort. 50 healthy participants took part in a cross-over study and received prolonged (1800 pulses) iTBS targeting the LDLPFC, cerebellar vermis, and sham iTBS. Mixed effects repeated measures models examined cognitive and event-related potentials (ERPs) from 2-back (P300, N200) and Stroop (N200, N450) tasks after stimulation. Exploratory non-parametric cluster-based permutation tests compared ERPs between conditions. There were no significant differences between conditions for behavioural and ERP outcomes on the 2-back and Stroop tasks. Exploratory cluster-based permutation tests of ERPs did not identify any significant differences between conditions. We did not find evidence that a single session of prolonged iTBS administered to either the LDLPFC or cerebellum could cause any cognitive or ERP changes compared to sham in a healthy sample.

Efficacy of a Lidocaine-Impregnated Elastrator Band for Castration and Tail Docking in Lambs.

The primary objective of this study was to demonstrate the non-inferiority between lidocaine-impregnated ligation bands (LLBs) and control bands (CBs) with respect to the efficacy of castration and tail docking. Secondary objectives were to compare castration and tail-docking success, evaluate local site reactions, and compare average daily gain (ADG) between the treatment groups. A total of 238 male lambs were enrolled and randomly assigned to receive LLBs or CBs on their tail and scrotum. Lambs were weighed, had a health assessment, and the band site was observed on -3, 7, 14, 21, 28, 35, and 42 days after the bands were applied. A linear regression model was built to assess average daily gain, whereas a repeated measures model was used to evaluate body weight differences at each of the measured timepoints. Furthermore, logistic regression models were used to evaluate associations with casting outcomes. Few differences were noted between treatment groups with respect to casting success for the scrotum and tail and ADG over the entire experimental period. Non-inferiority calculations demonstrated no differences in tail docking and scrotal casting success, with casting occurring for the majority of animals by d 21 and d 42 for castration and tail docking, respectively. However, lambs receiving LLBs gained more weight from d -3 to 7 (+0.03 kg/d; 95% CI: 0 to 0.07), which may be an indication of effective pain control during the first week following band application. Overall, the use of an LLB does not affect the time to successful casting of the tail and could improve short-term growth when compared to a control band. Further studies are needed to compare LLBs to multimodal methods of pain relief.